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1
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Boengler K, Mantuano B, Toledano S, Binah O, Schulz R. Overexpression of Cx43: Is It an Effective Approach for the Treatment of Cardiovascular Diseases? Biomolecules 2025; 15:370. [PMID: 40149906 PMCID: PMC11940156 DOI: 10.3390/biom15030370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 02/26/2025] [Accepted: 02/28/2025] [Indexed: 03/29/2025] Open
Abstract
In the heart, Connexin 43 (Cx43) is involved in intercellular communication through gap junctions and exosomes. In addition, Cx43-formed hemichannels at the plasma membrane are important for ion homeostasis and cellular volume regulation. Through its localization within nuclei and mitochondria, Cx43 influences the function of the respective organelles. Several cardiovascular diseases such as heart failure, ischemia/reperfusion injury, hypertrophic cardiomyopathy and arrhythmias are characterized by Cx43 downregulation and a dysregulated Cx43 function. Accordingly, a putative therapeutic approach of these diseases would include the induction of Cx43 expression in the damaged heart, albeit such induction may have both beneficial and detrimental effects. In this review we discuss the consequences of increasing cardiac Cx43 expression, and discuss this manipulation as a strategy for the treatment of cardiovascular diseases.
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Affiliation(s)
- Kerstin Boengler
- Institute of Physiology, Justus-Liebig University, 35392 Giessen, Germany
| | - Beatrice Mantuano
- Department of Clinical and Biological Sciences, University of Torino, 10125 Torino, Italy
| | - Shira Toledano
- Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3190601, Israel
| | - Ofer Binah
- Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3190601, Israel
| | - Rainer Schulz
- Institute of Physiology, Justus-Liebig University, 35392 Giessen, Germany
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2
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Fonseka O, Gare SR, Chen X, Zhang J, Alatawi NH, Ross C, Liu W. Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential. Cells 2025; 14:324. [PMID: 40072053 PMCID: PMC11899429 DOI: 10.3390/cells14050324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 02/07/2025] [Accepted: 02/17/2025] [Indexed: 03/15/2025] Open
Abstract
Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics of pathological cardiac remodeling, contributing to HF. The mechanisms involved in the development of cardiac remodeling and consequent HF are multifactorial, and in this review, the key underlying mechanisms are discussed. These have been divided into the following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, and oxidative stress; (ii) cardiac lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) stress; (iv) impaired autophagy; (v) cardiac inflammatory responses; (vi) programmed cell death, including apoptosis, pyroptosis, and ferroptosis; (vii) endothelial dysfunction; and (viii) defective cardiac contractility. Preclinical data suggest that there is merit in targeting the identified pathways; however, their clinical implications and outcomes regarding treating HF need further investigation in the future. Herein, we introduce the molecular mechanisms pivotal in the onset and progression of HF, as well as compounds targeting the related mechanisms and their therapeutic potential in preventing or rescuing HF. This, therefore, offers an avenue for the design and discovery of novel therapies for the treatment of HF.
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Affiliation(s)
| | | | | | | | | | | | - Wei Liu
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK; (O.F.); (S.R.G.); (X.C.); (J.Z.); (N.H.A.)
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3
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Jiang H, Zhang M, Li XM, Zhang NN, Du YS, Xia CY, Wang HQ, Zhang YN, Yang XY, Chen AP, Lai HQ, Yan X, Chu SF, Wang ZZ, Chen NH. The pathogenesis of depression: Roles of connexin 43-based gap junctions and inflammation. Eur J Pharmacol 2025; 989:177260. [PMID: 39798913 DOI: 10.1016/j.ejphar.2025.177260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 12/13/2024] [Accepted: 01/07/2025] [Indexed: 01/15/2025]
Abstract
BACKGROUND Depression is a leading chronic mental illness worldwide, characterized by anhedonia and pessimism. Connexin is a kind of widely distributed protein in the body. Connexin 43 (Cx43) plays an important role in the pathogenesis of depression. Growing evidence has indicated that inflammation is closely associated with neuropsychiatric diseases such as depression. Inflammation occurs in patients with mood disorders, and symptomatic relief after multiple treatments is often accompanied by proinflammatory restoration. In this study, we sought to determine the upstream and downstream relationship of Cx43 abnormalities and peripheral inflammation in inducing depression. METHODS AND RESULTS Gap27, as a Cx43 mimetic peptide, specifically blocks Cx43 gap junction channels in the brain. The mice were treated with injection of Gap27 into the prefrontal cortex (PFC), conditional knockout of Cx43 in the PFC, and lipopolysaccharide (LPS) intraperitoneal injection. Our results revealed that the treatments gave rise to the depressive-like behavior occurrence in mice, including reducing the sucrose preference and spontaneous activities, and increasing immobility time in the forced swimming test. Functional blockade of Cx43 induced abnormal expression of peripheral inflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor-α, IL-2, IL-10, and IL-18. Furthermore, depression associated with peripheral inflammation derived from LPS intraperitoneal injection significantly reduced the Cx43 expression and the diffusion distance of gap junction channel permeability dye in the PFC. CONCLUSION These results showed that blockade of Cx43 in the PFC and peripheral inflammation are complicatedly intertwined, and reinforcing each other during the induction of depression.
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Affiliation(s)
- Hong Jiang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Meng Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Xin-Mu Li
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Ning-Ning Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Yu-Sheng Du
- Hunan University of Traditional Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, 410208, Hunan, China
| | - Cong-Yuan Xia
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Hui-Qin Wang
- Hunan University of Traditional Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, 410208, Hunan, China
| | - Ya-Ni Zhang
- Institute of Clinical Pharmacology and Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Xue-Ying Yang
- Institute of Clinical Pharmacology and Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Ai-Ping Chen
- China Three Gorges University College of Medicine and Health Sciences, Yichang, 443002, China
| | - Hua-Qing Lai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Xu Yan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Shi-Feng Chu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Zhen-Zhen Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
| | - Nai-Hong Chen
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China; Hunan University of Traditional Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, 410208, Hunan, China.
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4
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Castro C, Patin J, Jajkiewicz C, Chizelle F, Cerpa CO, Tessier A, Le Pogam E, Fellah I, Baró I, Charpentier F, Derangeon M. Long QT syndrome type 3 gain-of-function of Na v1.5 increases ventricular fibroblasts proliferation and pro-fibrotic factors. Commun Biol 2025; 8:216. [PMID: 39934335 PMCID: PMC11814334 DOI: 10.1038/s42003-025-07636-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 01/30/2025] [Indexed: 02/13/2025] Open
Abstract
The long QT syndrome type 3 (LQT3) is a cardiac channelopathy caused by gain-of-function mutations in the SCN5A gene, encoding the sodium channel Nav1.5. As Nav1.5 is expressed in cardiomyocytes but also in cardiac fibroblasts, we investigated whether the LQT3-causing p.ΔQKP1507-1509 (ΔQKP) SCN5A mutation alters cardiac fibroblast phenotype. Primary cultured ventricular fibroblasts from Scn5a+/ΔQKP knock-in mice showed increased proliferation, survival, expression of transforming growth factor-β (TGF-β) and activation of its canonical pathway, and reduced α-smooth muscle actin expression. Ventricular tissue from Scn5a+/ΔQKP mice exhibited augmented fibroblast populations and fibrosis. Inhibiting TGF-β receptor, sodium current or Scn5a expression decreased Scn5a+/ΔQKP fibroblast proliferation, while veratridine increased proliferation of control fibroblasts, mimicking Nav1.5 gain-of-function. Lastly, abnormal calcium signaling underlied the increased proliferation of Scn5a+/ΔQKP fibroblasts. Our study shows that cardiac fibroblasts carrying the ΔQKP-SCN5A mutation exhibit an abnormal, proliferative phenotype, paving the way for better understanding the role of cardiac fibroblasts in LQT3.
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Affiliation(s)
- Claire Castro
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
- Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Justine Patin
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Cyrielle Jajkiewicz
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Franck Chizelle
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Cynthia Ore Cerpa
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Agnès Tessier
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Eva Le Pogam
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Imen Fellah
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Isabelle Baró
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Flavien Charpentier
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Mickaël Derangeon
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.
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Bader Eddin L, Nagoor Meeran MF, Kumar Jha N, Goyal SN, Ojha S. Isoproterenol mechanisms in inducing myocardial fibrosis and its application as an experimental model for the evaluation of therapeutic potential of phytochemicals and pharmaceuticals. Animal Model Exp Med 2025; 8:67-91. [PMID: 39690876 PMCID: PMC11798751 DOI: 10.1002/ame2.12496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 08/14/2024] [Indexed: 12/19/2024] Open
Abstract
Cardiac injury initiates repair mechanisms and results in cardiac remodeling and fibrosis, which appears to be a leading cause of cardiovascular diseases. Cardiac fibrosis is characterized by the accumulation of extracellular matrix proteins, mainly collagen in the cardiac interstitium. Many experimental studies have demonstrated that fibrotic injury in the heart is reversible; therefore, it is vital to understand different molecular mechanisms that are involved in the initiation, progression, and resolution of cardiac fibrosis to enable the development of antifibrotic agents. Of the many experimental models, one of the recent models that has gained renewed interest is isoproterenol (ISP)-induced cardiac fibrosis. ISP is a synthetic catecholamine, sympathomimetic, and nonselective β-adrenergic receptor agonist. The overstimulated and sustained activation of β-adrenergic receptors has been reported to induce biochemical and physiological alterations and ultimately result in cardiac remodeling. ISP has been used for decades to induce acute myocardial infarction. However, the use of low doses and chronic administration of ISP have been shown to induce cardiac fibrosis; this practice has increased in recent years. Intraperitoneal or subcutaneous ISP has been widely used in preclinical studies to induce cardiac remodeling manifested by fibrosis and hypertrophy. The induced oxidative stress with subsequent perturbations in cellular signaling cascades through triggering the release of free radicals is considered the initiating mechanism of myocardial fibrosis. ISP is consistently used to induce fibrosis in laboratory animals and in cardiomyocytes isolated from animals. In recent years, numerous phytochemicals and synthetic molecules have been evaluated in ISP-induced cardiac fibrosis. The present review exclusively provides a comprehensive summary of the pathological biochemical, histological, and molecular mechanisms of ISP in inducing cardiac fibrosis and hypertrophy. It also summarizes the application of this experimental model in the therapeutic evaluation of natural as well as synthetic compounds to demonstrate their potential in mitigating myocardial fibrosis and hypertrophy.
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Affiliation(s)
- Lujain Bader Eddin
- Department of Pharmacology and Therapeutics, College of Medicine and Health SciencesUAE UniversityAl AinUnited Arab Emirates
| | - Mohamed Fizur Nagoor Meeran
- Department of Pharmacology and Therapeutics, College of Medicine and Health SciencesUAE UniversityAl AinUnited Arab Emirates
| | - Niraj Kumar Jha
- School of Bioengineering & BiosciencesLovely Professional UniversityPhagwaraIndia
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha UniversityChennaiIndia
| | - Samer N. Goyal
- Shri Vile Parle Kelvani Mandal's Institute of PharmacyDhuleMaharashtraIndia
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health SciencesUAE UniversityAl AinUnited Arab Emirates
- Zayed Bin Sultan Center for Health SciencesUnited Arab Emirates UniversityAl AinUnited Arab Emirates
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6
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Maalouf M, Gaffney AT, Bell BR, Shaw RM. Exploring the Potent Roles of an Internally Translated Truncated Connexin-43 Isoform. BIOLOGY 2024; 13:1046. [PMID: 39765713 PMCID: PMC11672902 DOI: 10.3390/biology13121046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/10/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025]
Abstract
Connexins are a family of transmembrane proteins that form membrane channels [...].
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Affiliation(s)
| | | | | | - Robin M. Shaw
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84132, USA
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7
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Sun M, Zhai S, Gao Y, Hu N, Wang R, Zhang R. Circ_0049979 ameliorates myocardial infarction through improving Cx43-mediated endothelial functions. Toxicol Appl Pharmacol 2024; 492:117121. [PMID: 39384044 DOI: 10.1016/j.taap.2024.117121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 09/26/2024] [Accepted: 10/04/2024] [Indexed: 10/11/2024]
Abstract
Endothelial injury is a fundamental pathogenesis of coronary atherosclerotic heart disease (CHD). Circular RNAs (circRNAs) are important post-transcriptional regulators in many human major diseases, including CHD. The aim of the present study was to explore the role of circ_0049979, a novel identified circRNA from ANO8 gene locus, in endothelial injury during CHD. We found that expression of circ_0049979 was reduced by ox-LDL treatment in HUVECs in a dose-dependent manner. Loss- and gain-of-function experiments demonstrated that knockdown of circ_0049979 decreased the capacities of proliferation, migration and tube formation in normal HUVECs. While, overexpression of circ_0049979 improved these capacities in both normal and ox-LDL-incubated HUVECs. Then, the online bioinformatic tool Circinteractome was used to predicted the target miRNAs of circ_0049979, and miR-653 was selected as the candidate. We demonstrated that miR-653 directly interacted with and was negatively regulated by circ_0049979, and played a negative role in regulating proliferation, migration and tube formation of HUVECs. In terms of the mechanism, miR-653 post-transcriptionally suppressed the expression of the gap junction protein 43 (Cx43), a key protein of endothelial tight junction. Finally, we verified that overexpression of circ_0049979 was able to alleviate plaque formation, lipid deposition, and endothelial cell apoptosis, as well as myocardial infarction, in coronary atherosclerotic mice in vivo. In conclusion, circ_0049979 plays a protective role in coronary atherosclerotic myocardial infarction by improving miR-653/Cx43-mediated endothelial functions.
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Affiliation(s)
- Meng Sun
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China; The Cardiology Department of First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Shaodong Zhai
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
| | - Yangyang Gao
- The First Clinical Medical College, Shanxi Medical University, Taiyuan 030001, China
| | - Nan Hu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
| | - Rui Wang
- The Cardiology Department of First Hospital of Shanxi Medical University, Taiyuan 030001, China.
| | - Ruiping Zhang
- The Radiology Department of Shanxi Provincial People's Hospital, The Fifth Hospital of Shanxi Medical University, Taiyuan 030001, China.
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8
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Wu Z, Chen L, Guo W, Wang J, Ni H, Liu J, Jiang W, Shen J, Mao C, Zhou M, Wan M. Oral mitochondrial transplantation using nanomotors to treat ischaemic heart disease. NATURE NANOTECHNOLOGY 2024; 19:1375-1385. [PMID: 38802669 DOI: 10.1038/s41565-024-01681-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 04/15/2024] [Indexed: 05/29/2024]
Abstract
Mitochondrial transplantation is an important therapeutic strategy for restoring energy supply in patients with ischaemic heart disease (IHD); however, it is limited by the invasiveness of the transplantation method and loss of mitochondrial activity. Here we report successful mitochondrial transplantation by oral administration for IHD therapy. A nitric-oxide-releasing nanomotor is modified on the mitochondria surface to obtain nanomotorized mitochondria with chemotactic targeting ability towards damaged heart tissue due to nanomotor action. The nanomotorized mitochondria are packaged in enteric capsules to protect them from gastric acid erosion. After oral delivery the mitochondria are released in the intestine, where they are quickly absorbed by intestinal cells and secreted into the bloodstream, allowing delivery to the damaged heart tissue. The regulation of disease microenvironment by the nanomotorized mitochondria can not only achieve rapid uptake and high retention of mitochondria by damaged cardiomyocytes but also maintains high activity of the transplanted mitochondria. Furthermore, results from animal models of IHD indicate that the accumulated nanomotorized mitochondria in the damaged heart tissue can regulate cardiac metabolism at the transcriptional level, thus preventing IHD progression. This strategy has the potential to change the therapeutic strategy used to treat IHD.
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Affiliation(s)
- Ziyu Wu
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Lin Chen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
| | - Wenyan Guo
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
| | - Jun Wang
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Haiya Ni
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jianing Liu
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wentao Jiang
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jian Shen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.
| | - Min Zhou
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.
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9
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Matin M, Joshi T, Wang D, Tzvetkov NT, Matin FB, Wierzbicka A, Jóźwik A, Horbańczuk JO, Atanasov AG. Effects of Ginger ( Zingiber officinale) on the Hallmarks of Aging. Biomolecules 2024; 14:940. [PMID: 39199328 PMCID: PMC11352747 DOI: 10.3390/biom14080940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/22/2024] [Accepted: 07/29/2024] [Indexed: 09/01/2024] Open
Abstract
Ginger (Zingiber officinale Roscoe) is broadly used as a traditional remedy and food ingredient, and numerous preclinical and clinical studies have demonstrated health benefits in a range of age-related disorders. Moreover, longevity-promoting effects have been demonstrated in several (preclinical) research models. With this work, we aimed to comprehensively review the reported effects of ginger and its bioactive constituents on the twelve established hallmarks of aging, with the ultimate goal of gaining a deeper understanding of the potential for future interventions in the area of longevity-extension and counteracting of aging-related diseases. The reviewed literature supports the favorable effects of ginger and some of its constituents on all twelve hallmarks of aging, with a particularly high number of animal research studies indicating counteraction of nutrient-sensing dysregulations, mitochondrial dysfunction, chronic inflammation, and dysbiosis. On this background, validation in human clinical trials is still insufficient or is entirely missing, with the exception of some studies indicating positive effects on deregulated nutrient-sensing, chronic inflammation, and dysbiosis. Thus, the existing body of literature clearly supports the potential of ginger to be further studied in clinical trials as a supplement for the promotion of both lifespan and health span.
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Affiliation(s)
- Maima Matin
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, 05-552 Magdalenka, Poland; (M.M.); (A.W.); (A.J.); (J.O.H.)
| | - Tanuj Joshi
- Department of Pharmaceutical Sciences, Bhimtal, Kumaun University, Nainital 263002, India;
| | - Dongdong Wang
- Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada;
| | - Nikolay T. Tzvetkov
- Department of Biochemical Pharmacology and Drug Design, Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria;
| | - Farhan Bin Matin
- Department of Pharmacy, East West University, Aftabnagar, Dhaka 1212, Bangladesh;
| | - Agnieszka Wierzbicka
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, 05-552 Magdalenka, Poland; (M.M.); (A.W.); (A.J.); (J.O.H.)
| | - Artur Jóźwik
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, 05-552 Magdalenka, Poland; (M.M.); (A.W.); (A.J.); (J.O.H.)
| | - Jarosław Olav Horbańczuk
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, 05-552 Magdalenka, Poland; (M.M.); (A.W.); (A.J.); (J.O.H.)
| | - Atanas G. Atanasov
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, 05-552 Magdalenka, Poland; (M.M.); (A.W.); (A.J.); (J.O.H.)
- Laboratory of Natural Products and Medicinal Chemistry (LNPMC), Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Thandalam, Chennai 602105, India
- Ludwig Boltzmann Institute Digital Health and Patient Safety, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria
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10
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Barreto BC, Neves MVGD, Cardoso CMA, Meira CS, Daltro PS, Figueira CP, Santos GC, Silva DN, Távora F, Neto JDDS, Macambira SG, Lampe PD, Coutinho KCDS, Kasai Brunswick TH, Ribeiro dos Santos R, Campos de Carvalho AC, Soares MBP. The effects of inflammation on connexin 43 in chronic Chagas disease cardiomyopathy. Front Immunol 2024; 15:1440662. [PMID: 39136016 PMCID: PMC11317259 DOI: 10.3389/fimmu.2024.1440662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/11/2024] [Indexed: 08/15/2024] Open
Abstract
Background Cardiac arrhythmias are the main cause of sudden death due to Chronic Chagasic Cardiomyopathy (CCC). Here we investigated alterations in connexin 43 (Cx43) expression and phosphorylation in cardiomyocytes as well as associations with cardiac arrhythmias in CCC. Methods C57Bl/6 mice infected with Trypanosoma cruzi underwent cardiac evaluations at 6 and 12 months after infection via treadmill testing and EKG. Histopathology, cytokine gene expression, and distribution of total Cx43 and its phosphorylated forms Cx43S368 and Cx43S325/328/330 were investigated. Human heart samples obtained from subjects with CCC were submitted to immunofluorescence analysis. In vitro simulation of a pro-inflammatory microenvironment (IL-1β, TNF, and IFN-γ) was performed in H9c2 cells and iPSC-derived cardiomyocytes to evaluate Cx43 distribution, action potential duration, and Lucifer Yellow dye transfer. Results Mice chronically infected with T. cruzi exhibited impaired cardiac function associated with increased inflammation, fibrosis and upregulated IL-1β, TNF, and IFN-γ gene expression. Confocal microscopy revealed altered total Cx43, Cx43S368 and Cx43S325/328/330 localization and phosphorylation patterns in CCC, with dispersed staining outside the intercalated disc areas, i.e., in lateral membranes and the cytoplasm. Reduced co-localization of total Cx43 and N-cadherin was observed in the intercalated discs of CCC mouse hearts compared to controls. Similar results were obtained in human CCC heart samples, which showed Cx43 distribution outside the intercalated discs. Stimulation of human iPSC-derived cardiomyocytes or H9c2 cells with IL-1β, TNF, and IFN-γ induced alterations in Cx43 localization, reduced action potential duration and dye transfer between adjacent cells. Conclusion Heart inflammation in CCC affects the distribution and phosphorylation pattern of Cx43, which may contribute to the generation of conduction disturbances in Chagas disease.
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Affiliation(s)
- Breno Cardim Barreto
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil
- Department of Biochemistry and Biophysics, Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
- SENAI Institute of Innovation in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador, Bahia, Brazil
| | - Maria Vitória Gomes das Neves
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil
- Department of Biochemistry and Biophysics, Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
| | | | - Cássio Santana Meira
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil
- SENAI Institute of Innovation in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador, Bahia, Brazil
| | - Pâmela Santana Daltro
- Department of Biochemistry and Biophysics, Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
| | | | - Girlaine Café Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil
- Department of Biochemistry and Biophysics, Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
| | - Daniela Nascimento Silva
- SENAI Institute of Innovation in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador, Bahia, Brazil
| | - Fábio Távora
- Messejana Heart and Lung Hospital, Fortaleza, Brazil
| | | | - Simone Garcia Macambira
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil
- Department of Biochemistry and Biophysics, Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
| | - Paul D. Lampe
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | | | | | - Ricardo Ribeiro dos Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil
- SENAI Institute of Innovation in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador, Bahia, Brazil
| | | | - Milena Botelho Pereira Soares
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil
- SENAI Institute of Innovation in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador, Bahia, Brazil
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11
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Di Stolfo G, Mastroianno S, Soldato N, Massaro RS, De Luca G, Seripa D, Urbano M, Gravina C, Greco A, Siena P, Ciccone MM, Guaricci AI, Forleo C, Carella M, Potenza DR. The Role of TOMM40 in Cardiovascular Mortality and Conduction Disorders: An Observational Study. J Clin Med 2024; 13:3177. [PMID: 38892888 PMCID: PMC11172937 DOI: 10.3390/jcm13113177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/22/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024] Open
Abstract
Aims: TOMM40 single nucleotide polymorphism (SNP) rs2075650 consists of allelic variation c.275-31A > G and it has been linked to Alzheimer disease, apolipoprotein and cholesterol levels and other risk factors. However, data on its role in cardiovascular disorders are lacking. The first aim of the study is to evaluate mortality according to TOMM40 genotype in a cohort of selected patients affected by advanced atherosclerosis. Second aim was to investigate the relationship between Xg and AA alleles and the presence of conduction disorders and implantation of defibrillator (ICD) or pacemaker (PM) in our cohort. Materials and Methods: We enrolled 276 patients (mean age 70.16 ± 7.96 years) affected by hemodynamic significant carotid stenosis and/or ischemia of the lower limbs of II or III stadium Fontaine. We divided the population into two groups according to the genotype (Xg and AA carriers). We evaluated several electrocardiographic and echocardiographic parameters, including heart rate, rhythm, presence of right and left bundle branch block (LBBB and RBBB), PR interval, QRS duration and morphology, QTc interval, and left ventricular ejection fraction (LVEF). We clinically followed these patients for 82.53 ± 30.02 months and we evaluated the incidence of cardiovascular events, number of deaths and PM/ICD implantations. Results: We did not find a difference in total mortality between Xg and AA carriers (16.3 % vs. 19.4%; p = 0.62). However, we found a higher mortality for fatal cardiovascular events in Xg carriers (8.2% vs. 4.4%; HR = 4.53, 95% CI 1.179-17.367; p = 0.04) with respect to AA carriers. We noted a higher percentage of LBBB in Xg carriers (10.2% vs. 3.1%, p = 0.027), which was statistically significant. Presence of right bundle branch block (RBBB) was also higher in Xg (10.2% vs. 4.4%, p = 0.10), but without reaching statistically significant difference compared to AA patients. We did not observe significant differences in heart rate, presence of sinus rhythm, number of device implantations, PR and QTc intervals, QRS duration and LVEF between the two groups. At the time of enrolment, we observed a tendency for device implant in Xg carriers at a younger age compared to AA carriers (58.50 ± 0.71 y vs. 72.14 ± 11.11 y, p = 0.10). During the follow-up, we noted no statistical difference for new device implantations in Xg respect to AA carriers (8.2% vs. 3.5%; HR = 2.384, 95% CI 0.718-7.922; p = 0.156). The tendency to implant Xg at a younger age compared to AA patients was confirmed during follow-up, but without reaching a significant difference(69.50 ± 2.89 y vs. 75.63 ± 8.35 y, p = 0.074). Finally, we pointed out that Xg carriers underwent device implantation 7.27 ± 4.43 years before AA (65.83 ± 6.11 years vs. 73.10 ± 10.39 years) and that difference reached a statistically significant difference (p = 0.049) when we considered all patients, from enrollment to follow-up. Conclusions: In our study we observed that TOMM40 Xg patients affected by advanced atherosclerosis have a higher incidence of developing fatal cardiovascular events, higher incidence of LBBB and an earlier age of PM or ICD implantations, as compared to AA carriers. Further studies will be needed to evaluate the genomic contribution of TOMM40 SNPs to cardiovascular deaths and cardiac conduction diseases.
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Affiliation(s)
- Giuseppe Di Stolfo
- Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (S.M.); (R.S.M.); (G.D.L.); (D.R.P.)
| | - Sandra Mastroianno
- Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (S.M.); (R.S.M.); (G.D.L.); (D.R.P.)
| | - Nicolò Soldato
- University Cardiology Unit, Department of Interdisciplinary Medicine, Policlinic University Hospital, 70124 Bari, BA, Italy; (N.S.); (P.S.); (M.M.C.); (A.I.G.); (C.F.)
| | - Raimondo Salvatore Massaro
- Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (S.M.); (R.S.M.); (G.D.L.); (D.R.P.)
| | - Giovanni De Luca
- Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (S.M.); (R.S.M.); (G.D.L.); (D.R.P.)
| | - Davide Seripa
- Complex Structure of Geriatrics, Medical Sciences Department, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (D.S.); (M.U.); (C.G.); (A.G.)
| | - Maria Urbano
- Complex Structure of Geriatrics, Medical Sciences Department, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (D.S.); (M.U.); (C.G.); (A.G.)
| | - Carolina Gravina
- Complex Structure of Geriatrics, Medical Sciences Department, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (D.S.); (M.U.); (C.G.); (A.G.)
| | - Antonio Greco
- Complex Structure of Geriatrics, Medical Sciences Department, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (D.S.); (M.U.); (C.G.); (A.G.)
| | - Paola Siena
- University Cardiology Unit, Department of Interdisciplinary Medicine, Policlinic University Hospital, 70124 Bari, BA, Italy; (N.S.); (P.S.); (M.M.C.); (A.I.G.); (C.F.)
| | - Marco Matteo Ciccone
- University Cardiology Unit, Department of Interdisciplinary Medicine, Policlinic University Hospital, 70124 Bari, BA, Italy; (N.S.); (P.S.); (M.M.C.); (A.I.G.); (C.F.)
| | - Andrea Igoren Guaricci
- University Cardiology Unit, Department of Interdisciplinary Medicine, Policlinic University Hospital, 70124 Bari, BA, Italy; (N.S.); (P.S.); (M.M.C.); (A.I.G.); (C.F.)
| | - Cinzia Forleo
- University Cardiology Unit, Department of Interdisciplinary Medicine, Policlinic University Hospital, 70124 Bari, BA, Italy; (N.S.); (P.S.); (M.M.C.); (A.I.G.); (C.F.)
| | - Massimo Carella
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy;
| | - Domenico Rosario Potenza
- Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (S.M.); (R.S.M.); (G.D.L.); (D.R.P.)
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Xu H, Wang X, Zhu F, Guo S, Chao Z, Cao C, Lu Z, Zhu H, Wang M, Zhu F, Yang J, Zeng R, Yao Y. Comprehensive Pan-Cancer Analysis of Connexin 43 as a Potential Biomarker and Therapeutic Target in Human Kidney Renal Clear Cell Carcinoma (KIRC). MEDICINA (KAUNAS, LITHUANIA) 2024; 60:780. [PMID: 38792963 PMCID: PMC11123162 DOI: 10.3390/medicina60050780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/22/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024]
Abstract
Background and Objectives: Connexin 43 (Cx43) is involved in the transfer of small signaling molecules between neighboring cells, thereby exerting a major influence on the initiation and progression of tumorigenesis. However, there is a lack of systematic research on Cx43 expression and its predictive role in clinical diagnosis and prognosis in pan-cancer. Materials and Methods: Several biological databases were used to evaluate the expression levels of GJA1 (encoding Cx43) and its diagnostic and prognostic significance in pan-cancer. We targeted kidney renal clear cell carcinoma (KIRC) and investigated the relationship between GJA1 expression and different clinical features of KIRC patients. Then, we performed cell-based experiments to partially confirm our results and predicted several proteins that were functionally related to Cx43. Results: The expression of GJA1 has a high level of accuracy in predicting KIRC. High GJA1 expression was remarkably correlated with a favorable prognosis, and this expression was reduced in groups with poor clinical features in KIRC. Cell experiments confirmed the inhibitory effects of increased GJA1 expression on the migratory capacity of human renal cancer (RCC) cell lines, and protein-protein interaction (PPI) analysis predicted that CDH1 and CTNNB1 were closely related to Cx43. Conclusions: GJA1 could be a promising independent favorable prognostic factor for KIRC, and upregulation of GJA1 expression could inhibit the migratory capacity of renal cancer cells.
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Affiliation(s)
- Huzi Xu
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; (H.X.); (X.W.); (S.G.); (C.C.); (H.Z.); (M.W.); (F.Z.); (J.Y.)
| | - Xiuru Wang
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; (H.X.); (X.W.); (S.G.); (C.C.); (H.Z.); (M.W.); (F.Z.); (J.Y.)
| | - Fan Zhu
- Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Shuiming Guo
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; (H.X.); (X.W.); (S.G.); (C.C.); (H.Z.); (M.W.); (F.Z.); (J.Y.)
| | - Zheng Chao
- Division of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
| | - Chujin Cao
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; (H.X.); (X.W.); (S.G.); (C.C.); (H.Z.); (M.W.); (F.Z.); (J.Y.)
| | - Zhihui Lu
- Division of Nursing, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
| | - Han Zhu
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; (H.X.); (X.W.); (S.G.); (C.C.); (H.Z.); (M.W.); (F.Z.); (J.Y.)
| | - Meng Wang
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; (H.X.); (X.W.); (S.G.); (C.C.); (H.Z.); (M.W.); (F.Z.); (J.Y.)
| | - Fengming Zhu
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; (H.X.); (X.W.); (S.G.); (C.C.); (H.Z.); (M.W.); (F.Z.); (J.Y.)
| | - Juan Yang
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; (H.X.); (X.W.); (S.G.); (C.C.); (H.Z.); (M.W.); (F.Z.); (J.Y.)
| | - Rui Zeng
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; (H.X.); (X.W.); (S.G.); (C.C.); (H.Z.); (M.W.); (F.Z.); (J.Y.)
| | - Ying Yao
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; (H.X.); (X.W.); (S.G.); (C.C.); (H.Z.); (M.W.); (F.Z.); (J.Y.)
- Division of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
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13
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Mohammed D, Tavangar SM, Khodadoostan A, Mousavi SE, Dehpour AR, Jazaeri F. Effects of Gap 26, a Connexin 43 Inhibitor, on Cirrhotic Cardiomyopathy in Rats. Cureus 2024; 16:e59053. [PMID: 38680825 PMCID: PMC11055623 DOI: 10.7759/cureus.59053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2024] [Indexed: 05/01/2024] Open
Abstract
Introduction Cirrhotic cardiomyopathy (CCM) is recognized by impaired cardiac responsiveness to stress, prolonged QT interval, and systolic and diastolic dysfunctions. Connexins are a family of transmembrane proteins that play a key role in cardiac physiology. Connexin 43 (Cx43) inhibition showed cardio-protective effects. Peptide drug Cx43 inhibitor, Gap 26, could inhibit gap junction 43. This study was designed to evaluate the effects of a connexin mimetic peptide, Gap 26, in the CCM model in rats. Methods The cirrhosis was induced through carbon tetrachloride (CCl4). On day 56, electrocardiography (ECG) was recorded, spleen weight was measured, and tissue and serum samples were collected. Further, Cx43 mRNA expression in heart tissue was checked. Results The chronotropic responses decreased in the CCl4/saline and increased in the CCl4/Gap. The spleen weight, QTc interval, and brain natriuretic peptide (BNP), tumor necrosis factor-alpha (TNF-α), aspartate aminotransferase (AST), alanine transaminase (ALT), and malondialdehyde (MDA) levels elevated in the CCl4/saline, and the spleen weight, QTc interval, and MDA and ALT levels were reduced by Gap 26 treatment. The level of nuclear factor (erythroid-derived 2) factor 2 (Nrf2) decreased in the CCl4/saline. The Cx43 expression was downregulated in the CCl4/saline and upregulated with the Gap 26 treatment. Conclusion Gap 26 not only alleviated the chronotropic hyporesponsiveness and the severity of liver damage and upregulated the atrial Cx43 expression, but it also had an antioxidant effect on the heart.
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Affiliation(s)
- Dlshad Mohammed
- Pharmacology, Tehran University of Medical Sciences, Tehran, IRN
| | | | - Arash Khodadoostan
- Pharmacology, Shahid Beheshti University of Medical Sciences, Tehran, IRN
| | | | | | - Farahnaz Jazaeri
- Pharmacology, Tehran University of Medical Sciences, Tehran, IRN
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14
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García-Mendívil L, Pérez-Zabalza M, Oliver-Gelabert A, Vallejo-Gil JM, Fañanás-Mastral J, Vázquez-Sancho M, Bellido-Morales JA, Vaca-Núñez AS, Ballester-Cuenca C, Diez E, Ordovás L, Pueyo E. Interindividual Age-Independent Differences in Human CX43 Impact Ventricular Arrhythmic Risk. RESEARCH (WASHINGTON, D.C.) 2023; 6:0254. [PMID: 38023417 PMCID: PMC10650968 DOI: 10.34133/research.0254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 10/02/2023] [Indexed: 12/01/2023]
Abstract
Connexin 43 (CX43) is one of the major components of gap junctions, the structures responsible for the intercellular communication and transmission of the electrical impulse in the left ventricle. There is limited information on the histological changes of CX43 with age and their effect on electrophysiology, especially in humans. Here, we analyzed left ventricular biopsies from living donors starting at midlife to characterize age-related CX43 remodeling. We assessed its quantity, degree of lateralization, and spatial heterogeneity together with fibrotic deposition. We observed no significant age-related remodeling of CX43. Only spatial heterogeneity increased slightly with age, and this increase was better explained by biological age than by chronological age. Importantly, we found that CX43 features varied considerably among individuals in our population with no relevant relationship to age or fibrosis content, in contrast to animal species. We used our experimental results to feed computational models of human ventricular electrophysiology and to assess the effects of interindividual differences in specific features of CX43 and fibrosis on conduction velocity, action potential duration, and arrhythmogenicity. We found that larger amounts of fibrosis were associated with the highest arrhythmic risk, with this risk being increased when fibrosis deposition was combined with a reduction in CX43 amount and/or with an increase in CX43 spatial heterogeneity. These mechanisms underlying high arrhythmic risk in some individuals were not associated with age in our study population. In conclusion, our data rule out CX43 remodeling as an age-related arrhythmic substrate in the population beyond midlife, but highlight its potential as a proarrhythmic factor at the individual level, especially when combined with increased fibrosis.
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Affiliation(s)
- Laura García-Mendívil
- Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research,
University of Zaragoza, Zaragoza 50018, Spain
- BSICoS, Instituto de Investigación Sanitaria Aragón (IISA), Zaragoza 50018, Spain
| | - María Pérez-Zabalza
- Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research,
University of Zaragoza, Zaragoza 50018, Spain
- BSICoS, Instituto de Investigación Sanitaria Aragón (IISA), Zaragoza 50018, Spain
- Centro Universitario de la Defensa (CUD), Zaragoza 50090, Spain
| | - Antoni Oliver-Gelabert
- Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research,
University of Zaragoza, Zaragoza 50018, Spain
- BSICoS, Instituto de Investigación Sanitaria Aragón (IISA), Zaragoza 50018, Spain
| | - José María Vallejo-Gil
- Department of Cardiovascular Surgery,
University Hospital Miguel Servet, Zaragoza 50009, Spain
| | - Javier Fañanás-Mastral
- Department of Cardiovascular Surgery,
University Hospital Miguel Servet, Zaragoza 50009, Spain
| | - Manuel Vázquez-Sancho
- Department of Cardiovascular Surgery,
University Hospital Miguel Servet, Zaragoza 50009, Spain
| | | | | | - Carlos Ballester-Cuenca
- Department of Cardiovascular Surgery,
University Hospital Miguel Servet, Zaragoza 50009, Spain
| | - Emiliano Diez
- Institute of Experimental Medicine and Biology of Cuyo (IMBECU), CONICET, Mendoza 5500, Argentina
| | - Laura Ordovás
- Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research,
University of Zaragoza, Zaragoza 50018, Spain
- BSICoS, Instituto de Investigación Sanitaria Aragón (IISA), Zaragoza 50018, Spain
- Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID), Zaragoza 50018, Spain
| | - Esther Pueyo
- Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research,
University of Zaragoza, Zaragoza 50018, Spain
- BSICoS, Instituto de Investigación Sanitaria Aragón (IISA), Zaragoza 50018, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza 50018, Spain
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15
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Vaziri N, Marques D, Greenway SC, Bousman CA. The cellular mechanism of antipsychotic-induced myocarditis: A systematic review. Schizophr Res 2023; 261:206-215. [PMID: 37797362 DOI: 10.1016/j.schres.2023.09.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 04/23/2023] [Accepted: 09/24/2023] [Indexed: 10/07/2023]
Abstract
Antipsychotic drug-induced myocarditis is a serious and potentially fatal adverse drug reaction characterized by inflammation of the heart muscle (myocardium) that typically develops within the first month after commencing an antipsychotic drug. Although the precise mechanism of this severe adverse drug reaction is unknown, multiple theories have been proposed with varying levels of support from cellular or animal studies. We conducted a systematic review, in accordance with PRISMA guidelines, of published preclinical and clinical studies investigating the cellular mechanism by which antipsychotic drugs induce myocarditis. A literature search including all studies available before December 10, 2022, yielded 15 studies that met our inclusion criteria. Antipsychotics examined in the included studies included clozapine (n = 13), ziprasidone (n = 1), amisulpride (n = 1), haloperidol (n = 1), levomepromazine (n = 1), olanzapine (n = 1), and sertindole (n = 1). The evidence suggests several overlapping mechanistic cascades involving: (1) increased levels of catecholamines, (2) increased proinflammatory cytokines, (3) increased reactive oxygen species (ROS), (4) reduced antioxidant levels and activity, and (5) mitochondrial damage. Notable limitations such as, a focus on clozapine, sample heterogeneity, and use of supratherapeutic doses will need to be addressed in future studies. Discovery of the mechanism by which antipsychotic drugs induce myocarditis will allow the development of clinically-useful biomarkers to identify those patients at increased risk prior to drug exposure. The development or repurposing of therapeutics to prevent or treat drug-induced myocarditis will also be possible and this will enable increased and safe use of antipsychotics for those patients in need.
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Affiliation(s)
- Nazanin Vaziri
- Department of Medical Genetics, University of Calgary, Calgary, AB, Canada
| | - Diogo Marques
- Department of Medical Genetics, University of Calgary, Calgary, AB, Canada
| | - Steven C Greenway
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Chad A Bousman
- Department of Medical Genetics, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Psychiatry, University of Calgary, Calgary, AB, Canada; Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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16
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Malhan D, Schoenrock B, Yalçin M, Blottner D, Relόgio A. Circadian regulation in aging: Implications for spaceflight and life on earth. Aging Cell 2023; 22:e13935. [PMID: 37493006 PMCID: PMC10497835 DOI: 10.1111/acel.13935] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/30/2023] [Accepted: 07/07/2023] [Indexed: 07/27/2023] Open
Abstract
Alterations in the circadian system are characteristic of aging on Earth. With the decline in physiological processes due to aging, several health concerns including vision loss, cardiovascular disorders, cognitive impairments, and muscle mass loss arise in elderly populations. Similar health risks are reported as "red flag" risks among astronauts during and after a long-term Space exploration journey. However, little is known about the common molecular alterations underlying terrestrial aging and space-related aging in astronauts, and controversial conclusions have been recently reported. In light of the regulatory role of the circadian clock in the maintenance of human health, we review here the overlapping role of the circadian clock both on aging on Earth and spaceflight with a focus on the four most affected systems: visual, cardiovascular, central nervous, and musculoskeletal systems. In this review, we briefly introduce the regulatory role of the circadian clock in specific cellular processes followed by alterations in those processes due to aging. We next summarize the known molecular alterations associated with spaceflight, highlighting involved clock-regulated genes in space flown Drosophila, nematodes, small mammals, and astronauts. Finally, we discuss common genes that are altered in terms of their expression due to aging on Earth and spaceflight. Altogether, the data elaborated in this review strengthen our hypothesis regarding the timely need to include circadian dysregulation as an emerging hallmark of aging on Earth and beyond.
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Affiliation(s)
- Deeksha Malhan
- Institute for Systems Medicine and Faculty of Human MedicineMSH Medical School HamburgHamburgGermany
| | - Britt Schoenrock
- Institute of Integrative NeuroanatomyCharité‐Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
| | - Müge Yalçin
- Institute for Systems Medicine and Faculty of Human MedicineMSH Medical School HamburgHamburgGermany
- Institute for Theoretical Biology (ITB)Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
- Molecular Cancer Research Center (MKFZ), Medical Department of Hematology, Oncology, and Tumour Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
| | - Dieter Blottner
- Institute of Integrative NeuroanatomyCharité‐Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
- Neuromuscular System and Neuromuscular SignalingBerlin Center of Space Medicine & Extreme EnvironmentsBerlinGermany
| | - Angela Relόgio
- Institute for Systems Medicine and Faculty of Human MedicineMSH Medical School HamburgHamburgGermany
- Institute for Theoretical Biology (ITB)Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
- Molecular Cancer Research Center (MKFZ), Medical Department of Hematology, Oncology, and Tumour Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
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17
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Muneer R, Qazi REM, Fatima A, Ahmad W, Salim A, Dini L, Khan I. Wnt signaling pathway inhibitor promotes mesenchymal stem cells differentiation into cardiac progenitor cells in vitro and improves cardiomyopathy in vivo. World J Stem Cells 2023; 15:821-841. [PMID: 37700819 PMCID: PMC10494566 DOI: 10.4252/wjsc.v15.i8.821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/31/2023] [Accepted: 07/03/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND Cardiovascular diseases particularly myocardial infarction (MI) are the leading cause of mortality and morbidity around the globe. As cardiac tissue possesses very limited regeneration potential, therefore use of a potent small molecule, inhibitor Wnt production-4 (IWP-4) for stem cell differentiation into cardiomyocytes could be a promising approach for cardiac regeneration. Wnt pathway inhibitors may help stem cells in their fate determination towards cardiomyogenic lineage and provide better homing and survival of cells in vivo. Mesenchymal stem cells (MSCs) derived from the human umbilical cord have the potential to regenerate cardiac tissue, as they are easy to isolate and possess multilineage differentiation capability. IWP-4 may promote the differentiation of MSCs into the cardiac lineage. AIM To evaluate the cardiac differentiation ability of IWP-4 and its subsequent in vivo effects. METHODS Umbilical cord tissue of human origin was utilized to isolate the MSCs which were characterized by their morphology, immunophenotyping of surface markers specific to MSCs, as well as by tri-lineage differentiation capability. Cytotoxicity analysis was performed to identify the optimal concentration of IWP-4. MSCs were treated with 5 μM IWP-4 at two different time intervals. Differentiation of MSCs into cardiomyocytes was evaluated at DNA and protein levels. The MI rat model was developed. IWP-4 treated as well as untreated MSCs were implanted in the MI model, then the cardiac function was analyzed via echocardiography. MSCs were labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) dye for tracking, while the regeneration of infarcted myocardium was examined by histology and immunohistochemistry. RESULTS MSCs were isolated and characterized. Cytotoxicity analysis showed that IWP-4 was non-cytotoxic at 5 μM concentration. Cardiac specific gene and protein expression analyses exhibited more remarkable results in fourteen days treated group that was eventually selected for in vivo transplantation. Cardiac function was restored in the IWP-4 treated group in comparison to the MI group. Immunohistochemical analysis confirmed the homing of pre-differentiated MSCs that were labeled with DiI cell labeling dye. Histological analysis confirmed the significant reduction in fibrotic area, and improved left ventricular wall thickness in IWP-4 treated MSC group. CONCLUSION Treatment of MSCs with IWP-4 inhibits Wnt pathway and promotes cardiac differentiation. These pre-conditioned MSCs transplanted in vivo improved cardiac function by cell homing, survival, and differentiation at the infarcted region, increased left ventricular wall thickness, and reduced infarct size.
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Affiliation(s)
- Rabbia Muneer
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Rida-E-Maria Qazi
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Abiha Fatima
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Waqas Ahmad
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Luciana Dini
- Department of Biology and Biotechnologies Charles Darwin, Sapienza University of Rome, Rome 00185, Italy
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan.
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18
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Iqbal F, Johnston A, Wyse B, Rabani R, Mander P, Hoseini B, Wu J, Li RK, Gauthier-Fisher A, Szaraz P, Librach C. Combination human umbilical cord perivascular and endothelial colony forming cell therapy for ischemic cardiac injury. NPJ Regen Med 2023; 8:45. [PMID: 37626067 PMCID: PMC10457300 DOI: 10.1038/s41536-023-00321-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Cell-based therapeutics are promising interventions to repair ischemic cardiac tissue. However, no single cell type has yet been found to be both specialized and versatile enough to heal the heart. The synergistic effects of two regenerative cell types including endothelial colony forming cells (ECFC) and first-trimester human umbilical cord perivascular cells (FTM HUCPVC) with endothelial cell and pericyte properties respectively, on angiogenic and regenerative properties were tested in a rat model of myocardial infarction (MI), in vitro tube formation and Matrigel plug assay. The combination of FTM HUCPVCs and ECFCs synergistically reduced fibrosis and cardiomyocyte apoptosis, while promoting favorable cardiac remodeling and contractility. These effects were in part mediated by ANGPT2, PDGF-β, and VEGF-C. PDGF-β signaling-dependent synergistic effects on angiogenesis were also observed in vitro and in vivo. FTM HUCPVCs and ECFCs represent a cell combination therapy for promoting and sustaining vascularization following ischemic cardiac injury.
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Affiliation(s)
- Farwah Iqbal
- Create Fertility Centre, Toronto, ON, Canada
- Virginia Tech Carillion School of Medicine, Roanoke, VA, USA
| | | | | | | | | | | | - Jun Wu
- Toronto General Research Institute (TGRI), University Health Network (UHN), Toronto, ON, Canada
| | - Ren-Ke Li
- Toronto General Research Institute (TGRI), University Health Network (UHN), Toronto, ON, Canada
| | | | | | - Clifford Librach
- Create Fertility Centre, Toronto, ON, Canada.
- Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada.
- Institute of Medical Sciences, Department of Physiology, University of Toronto, Toronto, ON, Canada.
- Department of Obstetrics and Gynecology, Women's College Hospital, Toronto, ON, Canada.
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19
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Basara G, Bahcecioglu G, Ren X, Zorlutuna P. An Experimental and Numerical Investigation of Cardiac Tissue-Patch Interrelation. J Biomech Eng 2023; 145:081004. [PMID: 37337466 PMCID: PMC10321148 DOI: 10.1115/1.4062736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 06/21/2023]
Abstract
Tissue engineered cardiac patches have great potential as a regenerative therapy for myocardial infarction. Yet, the mutual interaction of cardiac patches with healthy tissue has not been completely understood. Here, we investigated the impact of acellular and cellular patches on a beating two-dimensional (2D) cardiac cell layer, and the effect of the beating of this layer on the cells encapsulated in the patch. We cultured human-induced pluripotent stem cell-derived cardiomyocytes (iCMs) on a coverslip and placed gelatin methacryloyl hydrogel alone or with encapsulated iCMs to create acellular and cellular patches, respectively. When the acellular patch was placed on the cardiac cell layer, the beating characteristics and Ca+2 handling properties reduced, whereas placing the cellular patch restored these characteristics. To better understand the effects of the cyclic contraction and relaxation induced by the beating cardiac cell layer on the patch placed on top of it, a simulation model was developed, and the calculated strain values were in agreement with the values measured experimentally. Moreover, this dynamic culture induced by the beating 2D iCM layer on the iCMs encapsulated in the cellular patch improved their beating velocity and frequency. Additionally, the encapsulated iCMs were observed to be coupled with the underlying beating 2D iCM layer. Overall, this study provides a detailed investigation on the mutual relationship of acellular/cellular patches with the beating 2D iCM layer, understanding of which would be valuable for developing more advanced cardiac patches.
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Affiliation(s)
- Gozde Basara
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, 225 Multidisciplinary Research Building, Notre Dame, IN 46556
| | - Gokhan Bahcecioglu
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, 108B Multidisciplinary Research Building, Notre Dame, IN 46556
| | - Xiang Ren
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556
| | - Pinar Zorlutuna
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556; Department of Chemical and Biomolecular Engineering, University of Notre Dame, 143 Multidisciplinary Research Building, Notre Dame, IN 46556
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20
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Mfarej MG, Hyland CA, Sanchez AC, Falk MM, Iovine MK, Skibbens RV. Cohesin: an emerging master regulator at the heart of cardiac development. Mol Biol Cell 2023; 34:rs2. [PMID: 36947206 PMCID: PMC10162415 DOI: 10.1091/mbc.e22-12-0557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 03/23/2023] Open
Abstract
Cohesins are ATPase complexes that play central roles in cellular processes such as chromosome division, DNA repair, and gene expression. Cohesinopathies arise from mutations in cohesin proteins or cohesin complex regulators and encompass a family of related developmental disorders that present with a range of severe birth defects, affect many different physiological systems, and often lead to embryonic fatality. Treatments for cohesinopathies are limited, in large part due to the lack of understanding of cohesin biology. Thus, characterizing the signaling networks that lie upstream and downstream of cohesin-dependent pathways remains clinically relevant. Here, we highlight alterations in cohesins and cohesin regulators that result in cohesinopathies, with a focus on cardiac defects. In addition, we suggest a novel and more unifying view regarding the mechanisms through which cohesinopathy-based heart defects may arise.
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Affiliation(s)
- Michael G. Mfarej
- Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015
| | - Caitlin A. Hyland
- Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015
| | - Annie C. Sanchez
- Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015
| | - Matthias M. Falk
- Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015
| | - M. Kathryn Iovine
- Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015
| | - Robert V. Skibbens
- Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015
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21
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Kursanov A, Balakina-Vikulova NA, Solovyova O, Panfilov A, Katsnelson LB. In silico analysis of the contribution of cardiomyocyte-fibroblast electromechanical interaction to the arrhythmia. Front Physiol 2023; 14:1123609. [PMID: 36969594 PMCID: PMC10036780 DOI: 10.3389/fphys.2023.1123609] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
Although fibroblasts are about 5–10 times smaller than cardiomyocytes, their number in the ventricle is about twice that of cardiomyocytes. The high density of fibroblasts in myocardial tissue leads to a noticeable effect of their electromechanical interaction with cardiomyocytes on the electrical and mechanical functions of the latter. Our work focuses on the analysis of the mechanisms of spontaneous electrical and mechanical activity of the fibroblast-coupled cardiomyocyte during its calcium overload, which occurs in a variety of pathologies, including acute ischemia. For this study, we developed a mathematical model of the electromechanical interaction between cardiomyocyte and fibroblasts and used it to simulate the impact of overloading cardiomyocytes. In contrast to modeling only the electrical interaction between cardiomyocyte and fibroblasts, the following new features emerge in simulations with the model that accounts for both electrical and mechanical coupling and mechano-electrical feedback loops in the interacting cells. First, the activity of mechanosensitive ion channels in the coupled fibroblasts depolarizes their resting potential. Second, this additional depolarization increases the resting potential of the coupled myocyte, thus augmenting its susceptibility to triggered activity. The triggered activity associated with the cardiomyocyte calcium overload manifests itself in the model either as early afterdepolarizations or as extrasystoles, i.e., extra action potentials and extra contractions. Analysis of the model simulations showed that mechanics contribute significantly to the proarrhythmic effects in the cardiomyocyte overloaded with calcium and coupled with fibroblasts, and that mechano-electrical feedback loops in both the cardiomyocyte and fibroblasts play a key role in this phenomenon.
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Affiliation(s)
- Alexander Kursanov
- Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russia
- Laboratory of Mathematical Modeling in Physiology and Medicine Based on Supercomputers, Ural Federal University, Ekaterinburg, Russia
| | - Nathalie A. Balakina-Vikulova
- Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russia
- Laboratory of Mathematical Modeling in Physiology and Medicine Based on Supercomputers, Ural Federal University, Ekaterinburg, Russia
| | - Olga Solovyova
- Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russia
- Laboratory of Mathematical Modeling in Physiology and Medicine Based on Supercomputers, Ural Federal University, Ekaterinburg, Russia
| | - Alexander Panfilov
- Laboratory of Mathematical Modeling in Physiology and Medicine Based on Supercomputers, Ural Federal University, Ekaterinburg, Russia
| | - Leonid B. Katsnelson
- Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russia
- Laboratory of Mathematical Modeling in Physiology and Medicine Based on Supercomputers, Ural Federal University, Ekaterinburg, Russia
- *Correspondence: Leonid B. Katsnelson,
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22
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Aging Hallmarks and the Role of Oxidative Stress. Antioxidants (Basel) 2023; 12:antiox12030651. [PMID: 36978899 PMCID: PMC10044767 DOI: 10.3390/antiox12030651] [Citation(s) in RCA: 139] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/26/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Aging is a complex biological process accompanied by a progressive decline in the physical function of the organism and an increased risk of age-related chronic diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. Studies have established that there exist nine hallmarks of the aging process, including (i) telomere shortening, (ii) genomic instability, (iii) epigenetic modifications, (iv) mitochondrial dysfunction, (v) loss of proteostasis, (vi) dysregulated nutrient sensing, (vii) stem cell exhaustion, (viii) cellular senescence, and (ix) altered cellular communication. All these alterations have been linked to sustained systemic inflammation, and these mechanisms contribute to the aging process in timing not clearly determined yet. Nevertheless, mitochondrial dysfunction is one of the most important mechanisms contributing to the aging process. Mitochondria is the primary endogenous source of reactive oxygen species (ROS). During the aging process, there is a decline in ATP production and elevated ROS production together with a decline in the antioxidant defense. Elevated ROS levels can cause oxidative stress and severe damage to the cell, organelle membranes, DNA, lipids, and proteins. This damage contributes to the aging phenotype. In this review, we summarize recent advances in the mechanisms of aging with an emphasis on mitochondrial dysfunction and ROS production.
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23
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Yang X, Sha X, Cao Y, Wang W, Shi J. Cx43 overexpression reduce the incidence of obstructive sleep apnea associated atrial fibrillation via the CaMKⅡγ/HIF-1 axis. Biochem Biophys Res Commun 2023; 659:62-71. [PMID: 37037067 DOI: 10.1016/j.bbrc.2023.03.084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 03/26/2023] [Accepted: 03/31/2023] [Indexed: 04/03/2023]
Abstract
BACKGROUND Previous studies by our group have demonstrated chronic intermittent hypoxia (CIH) can decrease connexin 43 (Cx43) protein expression and thus increase atrial fibrillation (AF) inducibility. Cardiac sympathetic denervation (CSD) can reduce AF and increase Cx43 expression, however, the underlying molecular mechanisms and signaling pathways are still unclear. METHODS AND RESULTS An obstructive sleep apnea (OSA) rat model in vivo experiments and CIH H9c2 cells model in vitro experiments were used to figure out the roles and underlying mechanisms of Cx43 on OSA-associated AF. In this study, we examined the expression of Cx43, CaMKⅡγ, Bax, Caspase 3, HIF-1 Bcl-2, Tunel, and CPB/p300, to discover the association between proteins and the mechanism of regulatory changes. The downstream proteins of Cx43 were calculated by gene sequencing and data analysis. We found Cx43 expression was significantly downregulated after CIH exposure in rat and H9c2 cells. Active caspase-3 and Bax at CIH+8 h group are high, but decreased at OE+8 h group. The Bcl-2 expression was higher in the N and OE+8 h group than CIH+8 h group. TUNEL-positive cells from the CIH+8 h group was markedly higher. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated Cx43 overexpression inhibited the CaMKIIγ expression, and CaMKIIγ was involved in the HIF-1 signaling pathway. In addition, we also found Cx43 overexpression remarkably decreased the HIF-1 protein and p300 mRNA expression, which inhibits the CaMKIIγ/HIF-1 signaling pathway. CONCLUSIONS Taken together, these results suggested Cx43 overexpression inhibits the expression of calcium/calmodulin dependent protein CaMKⅡγ via the Cx43/CaMKIIγ/HIF-1 axis, which finally reduces the myocardial apoptosis and incidence of AF.
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24
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Cross-ancestry genome-wide analysis of atrial fibrillation unveils disease biology and enables cardioembolic risk prediction. Nat Genet 2023; 55:187-197. [PMID: 36653681 PMCID: PMC9925380 DOI: 10.1038/s41588-022-01284-9] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 12/09/2022] [Indexed: 01/20/2023]
Abstract
Atrial fibrillation (AF) is a common cardiac arrhythmia resulting in increased risk of stroke. Despite highly heritable etiology, our understanding of the genetic architecture of AF remains incomplete. Here we performed a genome-wide association study in the Japanese population comprising 9,826 cases among 150,272 individuals and identified East Asian-specific rare variants associated with AF. A cross-ancestry meta-analysis of >1 million individuals, including 77,690 cases, identified 35 new susceptibility loci. Transcriptome-wide association analysis identified IL6R as a putative causal gene, suggesting the involvement of immune responses. Integrative analysis with ChIP-seq data and functional assessment using human induced pluripotent stem cell-derived cardiomyocytes demonstrated ERRg as having a key role in the transcriptional regulation of AF-associated genes. A polygenic risk score derived from the cross-ancestry meta-analysis predicted increased risks of cardiovascular and stroke mortalities and segregated individuals with cardioembolic stroke in undiagnosed AF patients. Our results provide new biological and clinical insights into AF genetics and suggest their potential for clinical applications.
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25
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Maneechote C, Kerdphoo S, Jaiwongkam T, Chattipakorn SC, Chattipakorn N. Chronic Pharmacological Modulation of Mitochondrial Dynamics Alleviates Prediabetes-Induced Myocardial Ischemia-Reperfusion Injury by Preventing Mitochondrial Dysfunction and Programmed Apoptosis. Cardiovasc Drugs Ther 2023; 37:89-105. [PMID: 34515894 DOI: 10.1007/s10557-021-07250-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/25/2021] [Indexed: 01/14/2023]
Abstract
PURPOSE There is an increasing body of evidence to show that impairment in mitochondrial dynamics including excessive fission and insufficient fusion has been observed in the pre-diabetic condition. In pre-diabetic rats with cardiac ischemia-reperfusion (I/R) injury, acute treatment with a mitochondria fission inhibitor (Mdivi-1) and a fusion promoter (M1) showed cardioprotection. However, the potential preventive effects of chronic Mdivi-1 and M1 treatment in a pre-diabetic model of cardiac I/R have never been elucidated. METHODS Male Wistar rats (n = 40) were fed with a high-fat diet (HFD) for 12 weeks to induce prediabetes. Then, all pre-diabetic rats received the following treatments daily via intraperitoneal injection for 2 weeks: (1) HFDV (Vehicle, 0.1% DMSO); (2) HFMdivi1 (Mdivi-1 1.2 mg/kg); (3) HFM1 (M1 2 mg/kg); and (4) HFCom (Mdivi-1 + M1). At the end of treatment protocols, all rats underwent 30 min of coronary artery ligation followed by reperfusion for 120 min. RESULTS Chronic Mdivi-1, M1, and the combined treatment showed markedly improved cardiac mitochondrial function and dynamic control, leading to a decrease in cardiac arrhythmias, myocardial cell death, and infarct size (49%, 42%, and 51% reduction for HFMdivi1, HFM1, and HFCom, respectively vs HFDV). All of these treatments improved cardiac function following cardiac I/R injury in pre-diabetic rats. CONCLUSION Chronic inhibition of mitochondrial fission and promotion of fusion exerted cardioprevention in prediabetes with cardiac I/R injury through the relief of cardiac mitochondrial dysfunction and dynamic alterations, and reduction in myocardial infarction, thus improving cardiac function.
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Affiliation(s)
- Chayodom Maneechote
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Sasiwan Kerdphoo
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Thidarat Jaiwongkam
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
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26
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Wu K, Wang Y, Yang H, Chen Y, Lu K, Wu Y, Liu C, Zhang H, Meng H, Yu Q, Zhang Y, Shen Z. Injectable Decellularized Extracellular Matrix Hydrogel Containing Stromal Cell-Derived Factor 1 Promotes Transplanted Cardiomyocyte Engraftment and Functional Regeneration after Myocardial Infarction. ACS APPLIED MATERIALS & INTERFACES 2023; 15:2578-2589. [PMID: 36598791 DOI: 10.1021/acsami.2c16682] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Transplantation of exogenous cardiomyocytes (CMs) is a hopeful method to treat myocardial infarction (MI). However, its clinical application still remains challenging due to low retention and survival rates of the transplanted cells. Herein, a stromal cell-derived factor 1 (SDF-1)-loaded injectable hydrogel based on a decellularized porcine extracellular matrix (dECM) is developed to encapsulate and deliver CMs locally to the infarct area of the heart. The soluble porcine cardiac dECM is composed of similar components such as the human cardiac ECM, which could be self-assembled into a nanofibrous hydrogel at physiological temperature to improve the retention of transplanted CMs. Furthermore, the chemokine SDF-1 could recruit endogenous cells to promote angiogenesis, mitigating the ischemic microenvironment and improving the survival of CMs. The results in vitro show that this composite hydrogel exhibits good biocompatibility, anti-apoptosis property, and chemotactic effects for mesenchymal stromal cells and endothelial cells through SDF-1-CXCR4 axis. Moreover, intramyocardial injection of this composite hydrogel to the infarcted area leads to the promotion of angiogenesis and inhibition of fibrosis, reducing the infarction size and improving the cardiac function. The combination of natural biomaterials, exogenous cells, and bioactive factors shows potential for MI treatment in the clinical application.
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Affiliation(s)
- Kui Wu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215007, P. R. China
- Department of Cardiovascular Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, P. R. China
| | - Yuanyuan Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215007, P. R. China
| | - Hong Yang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215007, P. R. China
| | - Yihuan Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215007, P. R. China
| | - Kunyan Lu
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China
| | - Yong Wu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215007, P. R. China
| | - Chunxia Liu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215007, P. R. China
| | - Haixin Zhang
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China
| | - Hanyu Meng
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215007, P. R. China
| | - Qian Yu
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China
| | - Yanxia Zhang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215007, P. R. China
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215007, P. R. China
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Bugiardini E, Nunes AM, Oliveira‐Santos A, Dagda M, Fontelonga TM, Barraza‐Flores P, Pittman AM, Morrow JM, Parton M, Houlden H, Elliott PM, Syrris P, Maas RP, Akhtar MM, Küsters B, Raaphorst J, Schouten M, Kamsteeg E, van Engelen B, Hanna MG, Phadke R, Lopes LR, Matthews E, Burkin DJ. Integrin α7 Mutations Are Associated With Adult-Onset Cardiac Dysfunction in Humans and Mice. J Am Heart Assoc 2022; 11:e026494. [PMID: 36444867 PMCID: PMC9851448 DOI: 10.1161/jaha.122.026494] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 11/02/2022] [Indexed: 11/30/2022]
Abstract
Background Integrin α7β1 is a major laminin receptor in skeletal and cardiac muscle. In skeletal muscle, integrin α7β1 plays an important role during muscle development and has been described as an important modifier of skeletal muscle diseases. The integrin α7β1 is also highly expressed in the heart, but its precise role in cardiac function is unknown. Mutations in the integrin α7 gene (ITGA7) have been reported in children with congenital myopathy. Methods and Results In this study, we described skeletal and cardiac muscle pathology in Itga7-/- mice and 5 patients from 2 unrelated families with ITGA7 mutations. Proband in family 1 presented a homozygous c.806_818del [p.S269fs] variant, and proband in family 2 was identified with 2 intron variants in the ITGA7 gene. The complete absence of the integrin α7 protein in muscle supports the ITGA7 mutations are pathogenic. We performed electrocardiography, echocardiography, or cardiac magnetic resonance imaging, and histological biopsy analyses in patients with ITGA7 deficiency and Itga7-/- mice. The patients exhibited cardiac dysrhythmia and dysfunction from the third decade of life and late-onset respiratory insufficiency, but with relatively mild limb muscle involvement. Mice demonstrated corresponding abnormalities in cardiac conduction and contraction as well as diaphragm muscle fibrosis. Conclusions Our data suggest that loss of integrin α7 causes a novel form of adult-onset cardiac dysfunction indicating a critical role for the integrin α7β1 in normal cardiac function and highlights the need for long-term cardiac monitoring in patients with ITGA7-related congenital myopathy.
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Affiliation(s)
- Enrico Bugiardini
- Queen Square Centre for Neuromuscular DiseasesQueen Square Institute of Neurology, UCL and National Hospital for Neurology and NeurosurgeryLondonUnited Kingdom
| | - Andreia M. Nunes
- Department of PharmacologyUniversity of Nevada Reno, School of Medicine, Center for Molecular MedicineRenoNV
| | - Ariany Oliveira‐Santos
- Department of PharmacologyUniversity of Nevada Reno, School of Medicine, Center for Molecular MedicineRenoNV
| | - Marisela Dagda
- Department of PharmacologyUniversity of Nevada Reno, School of Medicine, Center for Molecular MedicineRenoNV
| | - Tatiana M. Fontelonga
- Department of PharmacologyUniversity of Nevada Reno, School of Medicine, Center for Molecular MedicineRenoNV
| | - Pamela Barraza‐Flores
- Department of PharmacologyUniversity of Nevada Reno, School of Medicine, Center for Molecular MedicineRenoNV
| | - Alan M. Pittman
- Department of Neuromuscular DiseasesUCL Queen Square Institute of NeurologyLondonUnited Kingdom
- St George’sUniversity of LondonLondonUnited Kingdom
| | - Jasper M. Morrow
- Queen Square Centre for Neuromuscular DiseasesQueen Square Institute of Neurology, UCL and National Hospital for Neurology and NeurosurgeryLondonUnited Kingdom
| | - Matthew Parton
- Queen Square Centre for Neuromuscular DiseasesQueen Square Institute of Neurology, UCL and National Hospital for Neurology and NeurosurgeryLondonUnited Kingdom
| | - Henry Houlden
- Department of Neuromuscular DiseasesUCL Queen Square Institute of NeurologyLondonUnited Kingdom
| | - Perry M. Elliott
- Barts Heart Centre, Barts Health NHS TrustLondonUnited Kingdom
- Centre for Heart Muscle DiseaseInstitute of Cardiovascular Science, University College LondonLondonUnited Kingdom
| | - Petros Syrris
- Centre for Heart Muscle DiseaseInstitute of Cardiovascular Science, University College LondonLondonUnited Kingdom
| | - Roderick P. Maas
- Department of Neurology, Donders Institute for Brain, Cognition and BehaviourRadboud University Medical CenterNijmegenThe Netherlands
| | - Mohammed M. Akhtar
- Barts Heart Centre, Barts Health NHS TrustLondonUnited Kingdom
- Centre for Heart Muscle DiseaseInstitute of Cardiovascular Science, University College LondonLondonUnited Kingdom
| | - Benno Küsters
- Department of PathologyRadboud University Medical CenterNijmegenThe Netherlands
| | - Joost Raaphorst
- Department of Neurology, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam NeuroscienceAmsterdamThe Netherlands
| | - Meyke Schouten
- Department of Human GeneticsRadboud University Medical CenterNijmegenThe Netherlands
| | - Erik‐Jan Kamsteeg
- Department of Human GeneticsRadboud University Medical CenterNijmegenThe Netherlands
| | - Baziel van Engelen
- Department of Neurology, Donders Institute for Brain, Cognition and BehaviourRadboud University Medical CenterNijmegenThe Netherlands
| | - Michael G. Hanna
- Queen Square Centre for Neuromuscular DiseasesQueen Square Institute of Neurology, UCL and National Hospital for Neurology and NeurosurgeryLondonUnited Kingdom
| | - Rahul Phadke
- Division of NeuropathologyUCL Institute of NeurologyLondonUnited Kingdom
- Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular DiseasesUCL Great Ormond Street Institute of Child HealthLondonUnited Kingdom
| | - Luis R. Lopes
- Barts Heart Centre, Barts Health NHS TrustLondonUnited Kingdom
- Centre for Heart Muscle DiseaseInstitute of Cardiovascular Science, University College LondonLondonUnited Kingdom
| | - Emma Matthews
- The Atkinson Morley Neuromuscular Centre and Regional Neurosciences CentreSt George’s University Hospitals NHS Foundation TrustLondonUnited Kingdom
- Molecular and Clinical Sciences Research Institute, St George’s University of LondonLondonUnited Kingdom
| | - Dean J. Burkin
- Department of PharmacologyUniversity of Nevada Reno, School of Medicine, Center for Molecular MedicineRenoNV
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Wang F, Gong Y, Chen T, Li B, Zhang W, Yin L, Zhao H, Tang Y, Wang X, Huang C. Maresin1 ameliorates ventricular remodelling and arrhythmia in mice models of myocardial infarction via NRF2/HO-1 and TLR4/NF-kB signalling. Int Immunopharmacol 2022; 113:109369. [DOI: 10.1016/j.intimp.2022.109369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/04/2022] [Accepted: 10/15/2022] [Indexed: 11/05/2022]
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Vitale E, Rosso R, Lo Iacono M, Cristallini C, Giachino C, Rastaldo R. Apelin-13 Increases Functional Connexin-43 through Autophagy Inhibition via AKT/mTOR Pathway in the Non-Myocytic Cell Population of the Heart. Int J Mol Sci 2022; 23:13073. [PMID: 36361860 PMCID: PMC9655608 DOI: 10.3390/ijms232113073] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/21/2022] [Accepted: 10/25/2022] [Indexed: 11/10/2023] Open
Abstract
Studies have shown a link between the downregulation of connexin 43 (Cx43), the predominant isoform in cardiac gap junctions, and high susceptibility to cardiac arrhythmias and cardiomyocyte death. Non-myocytic cells (NMCs), the most abundant component of the heart, exert multiple cardiac functions and represent an important therapeutic target for diseased cardiac tissue. A few studies have investigated the effect of Apelin-13, an endogenous peptide with a key role in various cardiovascular functions, on Cx43 expression in cardiomyocytes. However, it remained unknown whether Apelin-13 influences Cx43 expression in NMCs. Here, we found that in NMCs, Cx43 protein expression increased after Apelin-13 treatment (100 nM for 48 h). Furthermore, dye transfer assays proved that Apelin-13-treated NMCs had a greater ability to communicate with surrounding cardiomyocytes, and this effect was abrogated by carbenoxolone, a gap junction inhibitor. Interestingly, we showed that Apelin-13 increased Cx43 through autophagy inhibition, as proved by the upregulation of p62 and LC3I, acting as 3-MA, a well-known autophagy inhibitor. In addition, Apelin-13-induced AKT and mTOR phosphorylation was abolished by LY294002 and rapamycin inhibitors resulting in Cx43 increased suppression. These results open the possibility of targeting gap junctions in NMCs with Apelin-13 as an exciting therapeutic approach with great potential.
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Affiliation(s)
- Emanuela Vitale
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy
| | - Rachele Rosso
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy
| | - Marco Lo Iacono
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy
| | - Caterina Cristallini
- Institute for Chemical and Physical Processes, IPCF ss Pisa, CNR, 56126 Pisa, Italy
| | - Claudia Giachino
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy
| | - Raffaella Rastaldo
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy
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Matan D, Mobarrez F, Löfström U, Corbascio M, Ekström M, Hage C, Lyngå P, Persson B, Eriksson M, Linde C, Persson H, Wallén H. Extracellular vesicles in heart failure – A study in patients with heart failure with preserved ejection fraction or heart failure with reduced ejection fraction characteristics undergoing elective coronary artery bypass grafting. Front Cardiovasc Med 2022; 9:952974. [PMID: 36330003 PMCID: PMC9622760 DOI: 10.3389/fcvm.2022.952974] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/23/2022] [Indexed: 12/02/2022] Open
Abstract
Aims Extracellular vesicles (EVs) were investigated as potential biomarkers associated with heart failure (HF) pathophysiology in patients undergoing elective coronary artery bypass surgery characterized by HF phenotype. Materials and methods Patients with preoperative proxy-diagnoses of HF types i.e., preserved (HFpEF; n = 19) or reduced ejection fraction (HFrEF; n = 20) were studied and compared to patients with normal left ventricular function (n = 42). EVs in plasma samples collected from the coronary sinus, an arterial line, and from the right atrium were analyzed by flow cytometry. We studied EVs of presumed cardiomyocyte origin [EVs exposing Connexin-43 + Caveolin-3 (Con43 + Cav3) and Connexin-43 + Troponin T (Con43 + TnT)], of endothelial origin [EVs exposing VE-Cadherin (VE-Cad)] and EVs exposing inflammatory markers [myeloperoxidase (MPO) or pentraxin3 (PTX3)]. Results Median concentrations of EVs exposing Con43 + TnT and Con43 + Cav3 were approximately five to six times higher in coronary sinus compared to radial artery indicative of cardiac release. Patients with HFrEF had high trans-coronary gradients of both Con43 + TnT and Con43 + Cav3 EVs, whereas HFpEF had elevated gradients of Con43 + Cav3 EVs but lower gradients of Con43 + TnT. Coronary sinus concentrations of both Con43 + TnT and Con43 + Cav3 correlated significantly with echocardiographic and laboratory measures of HF. MPO-EV concentrations were around two times higher in the right atrium compared to the coronary sinus, and slightly higher in HFpEF than in HFrEF. EV concentrations of endothelial origin (VE-Cad) were similar in all three patient groups. Conclusion Con43 + TnT and Con43 + Cav3 EVs are released over the heart indicating cardiomyocyte origin. In HFrEF the EV release profile is indicative of myocardial injury and myocardial stress with elevated trans-coronary gradients of both Con43 + TnT and Con43 + Cav3 EVs, whereas in HFpEF the profile indicates myocardial stress with less myocardial injury.
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Affiliation(s)
- Dmitri Matan
- Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden
- Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
- *Correspondence: Dmitri Matan,
| | - Fariborz Mobarrez
- Division of Clinical Chemistry, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Ulrika Löfström
- Department of Medicine, Capio St. Göran Hospital, Stockholm, Sweden
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Matthias Corbascio
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Mattias Ekström
- Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden
- Department of Cardiology, Danderyd Hospital, Stockholm, Sweden
| | - Camilla Hage
- Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
- Division of Clinical Chemistry, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Patrik Lyngå
- Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden
| | - Bengt Persson
- Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Maria Eriksson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Linde
- Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
- Division of Clinical Chemistry, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Hans Persson
- Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden
- Department of Cardiology, Danderyd Hospital, Stockholm, Sweden
| | - Håkan Wallén
- Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden
- Department of Cardiology, Danderyd Hospital, Stockholm, Sweden
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Effect of WenXin KeLi on Improvement of Arrhythmia after Myocardial Infarction by Intervening PI3K-AKT-mTOR Autophagy Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:2022970. [PMID: 36212955 PMCID: PMC9536921 DOI: 10.1155/2022/2022970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/12/2022] [Accepted: 09/10/2022] [Indexed: 11/17/2022]
Abstract
Background Myocardial infarction (MI) is an acute and serious cardiovascular disease. Arrhythmia after MI can lead to sudden cardiac death, which seriously affects the survival outcome of patients. WenXin KeLi is a Chinese patent medicine for the treatment of arrhythmia in a clinic, which can significantly improve symptoms of palpitation and play an important role in reducing the risk of arrhythmia after MI. In this study, we aimed to explore the pharmacological mechanism of WenXin KeLi in protecting the heart. Methods The MI model was established by ligating the left coronary artery and the ventricular fibrillation threshold (VFT) was measured by electrical stimulation. The expression of connexin43 (CX43) and autophagy-related protein were measured by Western Blot, and correlation analysis was conducted to study the relationship between cardiac autophagy, CX43, and arrhythmia in rats after MI. The effects of WenXin KeLi on arrhythmia, cardiac structure, and function in MI rats were respectively observed by electrical stimulation, cardiac gross section, Masson staining, and cardiac ultrasound. The effects of WenXin KeLi on the expression of phosphoinositide 3 kinase-protein kinase B-mammalian targets of rapamycin (PI3K-AKT-mTOR) autophagy pathway and CX43 were observed by Western Blot. Results After 4 weeks of MI, the VFT in the model group was significantly reduced, the expression levels of yeast ATG6 homolog (Beclin1), microtubule-associated protein 1A/1B-light chain 3 (LC3II/LC3I), and p-CX43 (S368) significantly increased, the expression of sequestosome-1(P62) and CX43 significantly decreased. LC3II/LC3I and Beclin1 expression were significantly negatively correlated with the VFT, and the expression of P62 and CX43 were significantly positively correlated with the VFT. LC3II/LC3I and Beclin1 expression were negatively correlated with CX43 expression, while P62 expression was positively correlated with CX43 expression. WenXin KeLi could significantly increase the VFT, reduce the deposition of collagen fibers, and increase the index levels of the left ventricular end-diastolic anterior wall (LVEDAW), interventricular septum end-diastolic (IVSED), left ventricular end-systolic anterior wall (LVESAW), interventricular septum end-systolic (IVSES), left ventricular end-diastolic posterior wall (LVEDPW), left ventricular end-systolic posterior wall (LVESPW), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and reduce the index levels of the left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). WenXin KeLi could increase the expression of CX43, P62, AKT, p-PI3K, p-AKT (308), p-AKT (473), and p-mTOR and decrease the expression of LC3II/LC3I and Beclin1. Conclusion WenXin KeLi can activate the PI3K-AKT-mTOR signaling pathway, improve cardiac autophagy and Cx43 expression in rats after MI, reduce the risk of arrhythmia after MI, and play a cardioprotective role.
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Towards a Better Understanding of Genotype-Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction. Int J Mol Sci 2022; 23:ijms231810765. [PMID: 36142674 PMCID: PMC9503274 DOI: 10.3390/ijms231810765] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/17/2022] Open
Abstract
Genetic variants in gene-encoding proteins involved in cell−cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics. The genotype−phenotype correlation, however, remains poorly understood. By providing an overview of variants that are assessed for a functional protein pathology, we show that this number (n = 115) is low compared to the number of variants that are assessed by in silico algorithms (>5000). As expected, there is a mismatch between the prediction of variant pathogenicity and the prediction of the functional effect compared to the real functional evidence. Aiding to improve genotype−phenotype correlations, we separate variants into ‘protein reducing’ or ‘altered protein’ variants and provide general conclusions about the skin and heart phenotype involved. We conclude by stipulating that adequate prognoses can only be given, and targeted therapies can only be designed, upon full knowledge of the protein pathology through functional investigation.
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Su XL, Wang SH, Komal S, Cui LG, Ni RC, Zhang LR, Han SN. The caspase-1 inhibitor VX765 upregulates connexin 43 expression and improves cell-cell communication after myocardial infarction via suppressing the IL-1β/p38 MAPK pathway. Acta Pharmacol Sin 2022; 43:2289-2301. [PMID: 35132192 PMCID: PMC9433445 DOI: 10.1038/s41401-021-00845-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 12/15/2021] [Indexed: 02/04/2023]
Abstract
Connexin 43 (Cx43) is the most important protein in the gap junction channel between cardiomyocytes. Abnormalities of Cx43 change the conduction velocity and direction of cardiomyocytes, leading to reentry and conduction block of the myocardium, thereby causing arrhythmia. It has been shown that IL-1β reduces the expression of Cx43 in astrocytes and cardiomyocytes in vitro. However, whether caspase-1 and IL-1β affect connexin 43 after myocardial infarction (MI) is uncertain. In this study we investigated the effects of VX765, a caspase-1 inhibitor, on the expression of Cx43 and cell-to-cell communication after MI. Rats were treated with VX765 (16 mg/kg, i.v.) 1 h before the left anterior descending artery (LAD) ligation, and then once daily for 7 days. The ischemic heart was collected for histochemical analysis and Western blot analysis. We showed that VX765 treatment significantly decreased the infarct area, and alleviated cardiac dysfunction and remodeling by suppressing the NLRP3 inflammasome/caspase-1/IL-1β expression in the heart after MI. In addition, VX765 treatment markedly raised Cx43 levels in the heart after MI. In vitro experiments were conducted in rat cardiac myocytes (RCMs) stimulated with the supernatant from LPS/ATP-treated rat cardiac fibroblasts (RCFs). Pretreatment of the RCFs with VX765 (25 μM) reversed the downregulation of Cx43 expression in RCMs and significantly improved intercellular communication detected using a scrape-loading/dye transfer assay. We revealed that VX765 suppressed the activation of p38 MAPK signaling in the heart tissue after MI as well as in RCMs stimulated with the supernatant from LPS/ATP-treated RCFs. Taken together, these data show that the caspase-1 inhibitor VX765 upregulates Cx43 expression and improves cell-to-cell communication in rat heart after MI via suppressing the IL-1β/p38 MAPK pathway.
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Affiliation(s)
- Xue-Ling Su
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Shu-Hui Wang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Sumra Komal
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Liu-Gen Cui
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Rui-Cong Ni
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Li-Rong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Sheng-Na Han
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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Coscarella IL, Landim-Vieira M, Pinto JR, Chelko SP. Arrhythmogenic Cardiomyopathy: Exercise Pitfalls, Role of Connexin-43, and Moving beyond Antiarrhythmics. Int J Mol Sci 2022; 23:ijms23158753. [PMID: 35955883 PMCID: PMC9369094 DOI: 10.3390/ijms23158753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/28/2022] [Accepted: 08/03/2022] [Indexed: 12/11/2022] Open
Abstract
Arrhythmogenic Cardiomyopathy (ACM), a Mendelian disorder that can affect both left and right ventricles, is most often associated with pathogenic desmosomal variants that can lead to fibrofatty replacement of the myocardium, a pathological hallmark of this disease. Current therapies are aimed to prevent the worsening of disease phenotypes and sudden cardiac death (SCD). Despite the use of implantable cardioverter defibrillators (ICDs) there is no present therapy that would mitigate the loss in electrical signal and propagation by these fibrofatty barriers. Recent studies have shown the influence of forced vs. voluntary exercise in a variety of healthy and diseased mice; more specifically, that exercised mice show increased Connexin-43 (Cx43) expression levels. Fascinatingly, increased Cx43 expression ameliorated the abnormal electrical signal conduction in the myocardium of diseased mice. These findings point to a major translational pitfall in current therapeutics for ACM patients, who are advised to completely cease exercising and already demonstrate reduced Cx43 levels at the myocyte intercalated disc. Considering cardiac dysfunction in ACM arises from the loss of cardiomyocytes and electrical signal conduction abnormalities, an increase in Cx43 expression-promoted by low to moderate intensity exercise and/or gene therapy-could very well improve cardiac function in ACM patients.
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Affiliation(s)
- Isabella Leite Coscarella
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32303, USA
| | - Maicon Landim-Vieira
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32303, USA
| | - José Renato Pinto
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32303, USA
| | - Stephen P. Chelko
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32303, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21215, USA
- Correspondence: ; Tel.: +1-850-644-2215
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Zhou Z, Chai W, Liu Y, Zhou M, Zhang X. Connexins and angiogenesis: Functional aspects, pathogenesis, and emerging therapies (Review). Int J Mol Med 2022; 50:110. [PMID: 35762312 PMCID: PMC9256078 DOI: 10.3892/ijmm.2022.5166] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/08/2022] [Indexed: 11/20/2022] Open
Abstract
Connexins (Cxs) play key roles in cellular communication. By facilitating metabolite exchange or interfering with distinct signaling pathways, Cxs affect cell homeostasis, proliferation, and differentiation. Variations in the activity and expression of Cxs have been linked to numerous clinical conditions including carcinomas, cardiac disorders, and wound healing. Recent discoveries on the association between Cxs and angiogenesis have sparked interest in Cx-mediated angiogenesis due to its essential functions in tissue formation, wound repair, tumor growth, and metastasis. It is now widely recognized that understanding the association between Cxs and angiogenesis may aid in the development of new targeted therapies for angiogenic diseases. The aim of the present review was to provide a comprehensive overview of Cxs and Cx-mediated angiogenesis, with a focus on therapeutic implications.
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Affiliation(s)
- Zizi Zhou
- Department of Cardio‑Thoracic Surgery, Shenzhen University General Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Wenxiang Chai
- Department of Cardio‑Thoracic Surgery, Shenzhen University General Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Yi Liu
- Department of Cardio‑Thoracic Surgery, Shenzhen University General Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Meng Zhou
- Department of Cardio‑Thoracic Surgery, Shenzhen University General Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Xiaoming Zhang
- Department of Cardio‑Thoracic Surgery, Shenzhen University General Hospital, Shenzhen, Guangdong 518055, P.R. China
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Abstract
Purpose of Review The advent of induced pluripotent stem cells (iPSC) has paved the way for new in vitro models of human cardiomyopathy. Herein, we will review existing models of disease as well as strengths and limitations of the system. Recent Findings Preclinical studies have now demonstrated that iPSCs generated from patients with both acquired or heritable genetic diseases retain properties of the disease in vitro and can be used as a model to study novel therapeutics. iPSCs can be differentiated in vitro into the cardiomyocyte lineage into cells resembling adult ventricular myocytes that retain properties of cardiovascular disease from their respective donor. iPSC pluripotency allows for them to be frozen, stored, and continually used to generate iPSC-derived myocytes for future experiments without need for invasive procedures or repeat myocyte isolations to obtain animal or human cardiac tissues. Summary While not without their limitations, iPSC models offer new ways for studying patient-specific cardiomyopathies. iPSCs offer a high-throughput avenue for drug development, modeling of disease pathophysiology in vitro, and enabling experimental repair strategies without need for invasive procedures to obtain cardiac tissues.
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Yang HT, Li LL, Li SN, Wu JT, Chen K, Song WF, Zhang GB, Ma JF, Fu HX, Cao S, Gao CY, Hu J. MicroRNA-155 inhibition attenuates myocardial infarction-induced connexin 43 degradation in cardiomyocytes by reducing pro-inflammatory macrophage activation. Cardiovasc Diagn Ther 2022; 12:325-339. [PMID: 35800355 PMCID: PMC9253173 DOI: 10.21037/cdt-21-743] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 06/01/2022] [Indexed: 09/29/2023]
Abstract
BACKGROUND Degradation of pro-inflammatory macrophage-mediated connexin 43 (Cx43) plays an important role in post-myocardial infarction (MI) arrhythmogenesis, microRNA (miR)-155 produced by macrophages has been shown to mediate post-MI effects. We hypothesized that miR-155 inhibition attenuated MI-induced Cx43 degradation by reducing pro-inflammatory macrophage activation. METHODS MI was induced by permanent ligation of the left anterior descending coronary artery in male C57BL/6 mice. Lipopolysaccharide (LPS)-stimulated mice bone marrow-derived macrophages (BMDMs) and hypoxia-induced neonatal rat cardiomyocytes (NRCMs) were used in vitro models. qRT-PCR, Western-blot and immunofluorescence were used to analyze relevant indicators. RESULTS The expression levels of miR-155, interleukin-1 beta (IL-1β), and matrix metalloproteinase (MMP)7 were higher in MI mice and LPS-treated BMDMs than in the sham/control groups, treatment with a miR-155 antagomir reversed these effects. Moreover, miR-155 inhibition reduced ventricular arrhythmias incidence and improved cardiac function in MI mice. Cx43 expression was decreased in MI mice and hypoxia-exposed NRCMs, and hypoxia-induced Cx43 degradation in NRCMs was reduced by application of conditioned medium from LPS-induced BMDMs treated with the miR-155 antagomir, but increased by conditioned medium from BMDMs treated with a miR-155 agomir. Importantly, NRCMs cultured in conditioned medium from LPS-induced BMDMs transfected with small interfering RNA against IL-1β and MMP7 showed decreased hypoxia-mediated Cx43 degradation, and this effect also was diminished by BMDM treatment with the miR-155 agomir. Additionally, siRNA-mediated suppressor of cytokine signaling 1 (SOCS1) knockdown in LPS-induced BMDMs promoted Cx43 degradation in hypoxia-exposed NRCMs, and the effect was reduced by the miR-155 inhibition. CONCLUSIONS MiR-155 inhibition attenuated post-MI Cx43 degradation by reducing macrophage-mediated IL-1β and MMP7 expression through the SOCS1/nuclear factor-κB pathway.
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Affiliation(s)
- Hai-Tao Yang
- Heart Center of Henan Provincial People’s Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China
| | - Li-Li Li
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Song-Nan Li
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Jin-Tao Wu
- Heart Center of Henan Provincial People’s Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China
| | - Ke Chen
- Heart Center of Henan Provincial People’s Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China
| | - Wei-Feng Song
- Heart Center of Henan Provincial People’s Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China
| | - Guo-Bao Zhang
- Heart Center of Henan Provincial People’s Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China
| | - Ji-Fang Ma
- Heart Center of Henan Provincial People’s Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China
| | - Hai-Xia Fu
- Heart Center of Henan Provincial People’s Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China
| | - Sheng Cao
- Department of Ultrasound, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chuan-Yu Gao
- Heart Center of Henan Provincial People’s Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China
| | - Juan Hu
- Heart Center of Henan Provincial People’s Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China
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Gholami S, Mokhtari B, Badalzadeh R. Alpha-lipoic acid potentiates the anti-arrhythmic effects of ischemic postconditioning in the setting of cardiac ischemia/reperfusion injury in diabetic rats. J Diabetes Metab Disord 2022; 21:707-716. [PMID: 35673476 DOI: 10.1007/s40200-022-01034-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/15/2022] [Indexed: 01/13/2023]
Abstract
Background Prevention of lethal ventricular arrhythmias induced by myocardial ischemia/reperfusion (I/R) in diabetic patients is the major goal of cardioprotective strategies. Here, we aimed to examine the anti-arrhythmic effect of ischemic postconditioning (IPostC) and alpha-lipoic acid (ALA) in myocardial I/R injury of type-II diabetic rats, focusing on the involvement of connexin-43 and nitric oxide (NO) in this context. Methods Diabetes (duration of 12 weeks) was induced by high-fat diet and low dose of streptozotocin in thirty male Wistar rats (12 weeks old, 200-250 g). After mounting the hearts on the Langendorff apparatus, I/R was induced by the ligation of left anterior descending coronary artery for 35 min, and reperfusion for 60 min. ALA (100 mg/kg/day) was administered orally in diabetic rats for five weeks before I/R. IPostC was applied immediately at early reperfusion. The arrhythmias were evaluated according to the Lambeth convention. Connexin-43 expression and NO levels were assessed by western blotting and Griess calorimetric method, respectively. Results IPostC could not significantly decrease the number, duration, and incidence of premature ventricular contraction, ventricular tachycardia, and ventricular fibrillation, also the severity of arrhythmias in diabetic hearts. However, IPostC in combination with ALA-preconditioning significantly decreased the above mentioned parameters compared with untreated or monotherapies-received diabetic rats (P < 0.05 to P < 0.001). Furthermore, this combination therapy significantly increased connexin-43 expression and NO levels, compared with untreated diabetic rats (P < 0.01). Conclusion Preconditioning with ALA restored anti-arrhythmic effect of IPostC in diabetic hearts. Increased connexin-43 expression and NO levels may be the key players in this cardioprotection.
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Affiliation(s)
- Sanaz Gholami
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - Behnaz Mokhtari
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran.,Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - Reza Badalzadeh
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran.,Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
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Singhanat K, Apaijai N, Sumneang N, Maneechote C, Arunsak B, Chunchai T, Chattipakorn SC, Chattipakorn N. Therapeutic potential of a single-dose melatonin in the attenuation of cardiac ischemia/reperfusion injury in prediabetic obese rats. Cell Mol Life Sci 2022; 79:300. [PMID: 35588335 PMCID: PMC11072751 DOI: 10.1007/s00018-022-04330-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/24/2022] [Accepted: 04/27/2022] [Indexed: 01/05/2023]
Abstract
Although acute melatonin treatment effectively reduces cardiac ischemia/reperfusion (I/R) injury in lean rats by modulating melatonin receptor 2 (MT2), there is no information regarding the temporal effects of melatonin administration during cardiac I/R injury in prediabetic obese rats. Prediabetic obese rats induced by chronic consumption of a high-fat diet (HFD) were used. The rats underwent a cardiac I/R surgical procedure (30-min of ischemia, followed by 120-min of reperfusion) and were randomly assigned to receive either vehicle or melatonin treatment. In the melatonin group, rats were divided into 3 different subgroups: (1) pretreatment, (2) treatment during ischemic period, (3) treatment at the reperfusion onset. In the pretreatment subgroup either a nonspecific MT blocker (Luzindole) or specific MT2 blocker (4-PPDOT) was also given to the rats prior to melatonin treatment. Pretreatment with melatonin (10 mg/kg) effectively reduced cardiac I/R injury by reducing infarct size, arrhythmia, and LV dysfunction. Reduction in impaired mitochondrial function, mitochondrial dynamic balance, oxidative stress, defective autophagy, and apoptosis were observed in rats pretreated with melatonin. Unfortunately, the cardioprotective benefits were not observed when 10-mg/kg of melatonin was acutely administered to the rats after cardiac ischemia. Thus, we increased the dose of melatonin to 20 mg/kg, and it was administered to the rats during ischemia or at the onset of reperfusion. The results showed that 20-mg/kg of melatonin effectively reduced cardiac I/R injury to a similar extent to the 10-mg/kg pretreatment regimen. The MT2 blocker inhibited the protective effects of melatonin. Acute melatonin treatment during cardiac I/R injury exerted protective effects in prediabetic obese rats. However, a higher dose of melatonin is required when given after the onset of cardiac ischemia. These effects of melatonin were mainly mediated through activation of MT2.
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Affiliation(s)
- Kodchanan Singhanat
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nattayaporn Apaijai
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Natticha Sumneang
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Chayodom Maneechote
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Busarin Arunsak
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Titikorn Chunchai
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
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Hou J, Huang S, Long Y, Feng K, Shang L, Zhou Z, Yue Y, Huang X, Chen G, Wu Z. Disheveled binding antagonist of β-catenin 1 interacted with β-catenin and connexin 43 in human-induced pluripotent stem cells-derived cardiomyocytes. Bioengineered 2022; 13:11594-11601. [PMID: 35510412 PMCID: PMC9275970 DOI: 10.1080/21655979.2022.2070448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Previously, we demonstrated that the disheveled binding antagonist of β-catenin 1 (DACT1) was involved in atrial fibrillation by regulating the reorganization of connexin 43 and β-catenin in cardiomyocytes. Little is known, however, about DACT1 in human normal myocardial cells. Therefore, we used cardiomyocytes (CMs) derived from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to investigate the role of DACT1 and its connection with β-catenin and connexin 43. While the ESC-CMs and iPSC-CMs were differentiated using commercial differentiation kits, the cardiac-specific markers were detected by immunofluorescence. The expression level of DACT1 was detected using western blotting, whereas the interaction of DACT1 and connexin 43 or β-catenin was detected by immunofluorescence and co-immunoprecipitation (co-IP) assays. Both H1-CMs and SF-CMs were immunostained for cardiac-specific markers, including Troponin I, Troponin T, α-actinin, NKX2.5, and GATA6. While DACT1 was not expressed in both H1 ESCs and SF-iPSCs, it was, however, highly expressed in differentiated CMs, being also localized in the cytoplasm and the nucleus of differentiated CMs. Interestingly, the DACT1 expression in different nuclei was different in the same multinucleated cell. Moreover, DACT1 colocalized with β-catenin in both the cytoplasm and nucleus of differentiated CMs, and it also colocalized with connexin 43 in the perinuclear region and the gap junctions of differentiated CMs. Co-IP results showed that DACT1 could directly bind to β-catenin and connexin 43. Taken together, DACT1 interacted with β-catenin and connexin 43 in human-induced pluripotent stem cells-derived cardiomyocytes.
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Affiliation(s)
- Jian Hou
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Nhc Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China
| | - Suiqing Huang
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Nhc Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China
| | - Yan Long
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Nhc Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China
| | - Kangni Feng
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liqun Shang
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Nhc Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China
| | - Zhuoming Zhou
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Nhc Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China
| | - Yuan Yue
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Nhc Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China
| | - Xiaolin Huang
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Nhc Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China
| | - Guangxian Chen
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Nhc Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China
| | - Zhongkai Wu
- Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Nhc Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China
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Guan L, Yang Y, Liang JJ, Miao Y, Shang AY, Wang B, Wang YC, Ding M. ERGIC2 and ERGIC3 regulate the ER-to-Golgi transport of gap junction proteins in metazoans. Traffic 2022; 23:140-157. [PMID: 34994051 DOI: 10.1111/tra.12830] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 12/16/2021] [Accepted: 01/04/2022] [Indexed: 11/26/2022]
Abstract
The extremely dynamic life cycle of gap junction connections requires highly efficient intracellular trafficking system especially designed for gap junction proteins, but the underlying mechanisms are largely unknown. Here, we identified that the COPII-associated proteins ERGIC2 (ER-Golgi intermediate compartment) and ERGIC3 are specifically required for the efficient intracellular transport of gap junction proteins in both C. elegans and mice. In the absence of Ergic2 or Ergic3, gap junction proteins accumulate in the ER and Golgi apparatus and the size of endogenous gap junction plaques is reduced. Knocking out the Ergic2 or Ergic3 in mice results in heart enlargement and cardiac malfunction accompanied by reduced number and size of connexin 43 (Cx43) gap junctions. Invertebrates' gap junction protein innexins share no sequence similarity with vertebrates' connexins. However, ERGIC2 and ERGIC3 could bind to gap junction proteins in both worms and mice. Characterization of the highly specialized roles of ERGIC2 and ERGIC3 in metazoans reveals how the early secretory pathway could be adapted to facilitate the efficient transport for gap junction proteins in vivo. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Liying Guan
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yongzhi Yang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jing Jing Liang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yue Miao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Ang Yang Shang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Baolei Wang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Ying Chun Wang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Mei Ding
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
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Bandopadhyay S, Anand U, Gadekar VS, Jha NK, Gupta PK, Behl T, Kumar M, Shekhawat MS, Dey A. Dioscin: A review on pharmacological properties and therapeutic values. Biofactors 2022; 48:22-55. [PMID: 34919768 DOI: 10.1002/biof.1815] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/27/2021] [Indexed: 02/06/2023]
Abstract
Dioscin has gained immense popularity as a natural, bioactive steroid saponin, which offers numerous medical benefits. The growing global incidence of disease-associated morbidity and mortality continues to compromise human health, facilitating an increasingly urgent need for nontoxic, noninvasive, and efficient treatment alternatives. Natural compounds can contribute vastly to this field. Over recent years, studies have demonstrated the remarkable protective actions of dioscin against a variety of human malignancies, metabolic disorders, organ injuries, and viral/fungal infections. The successful usage of this phytocompound has been widely seen in medical treatment procedures under traditional Chinese medicine, and it is becoming progressively prevalent worldwide. This review provides an insight into the wide spectrum of pharmacological activities of dioscin, as reported and compiled in recent literature. The various novel approaches and applications of dioscin also verify the advantages exhibited by plant extracts against commercially available drugs, highlighting the potential of phytochemical agents like dioscin to be further incorporated into clinical practice.
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Affiliation(s)
| | - Uttpal Anand
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Vijaykumar Shivaji Gadekar
- Zoology Department, Sangola College (affiliated to Punyashlok Ahilyadevi Holkar Solapur University), Solapur, Maharashtra, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Piyush Kumar Gupta
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Tapan Behl
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India
| | - Manoj Kumar
- Chemical and Biochemical Processing Division, ICAR - Central Institute for Research on Cotton Technology, Mumbai, Maharashtra, India
| | - Mahipal S Shekhawat
- Plant Biotechnology Unit, Kanchi Mamunivar Government Institute for Postgraduate Studies and Research, Puducherry, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, West Bengal, India
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Jakubiak GK, Pawlas N, Cieślar G, Stanek A. Pathogenesis and Clinical Significance of In-Stent Restenosis in Patients with Diabetes. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:11970. [PMID: 34831726 PMCID: PMC8617716 DOI: 10.3390/ijerph182211970] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 11/11/2021] [Accepted: 11/13/2021] [Indexed: 12/13/2022]
Abstract
Diabetes mellitus (DM) is a strong risk factor for the development of cardiovascular diseases such as coronary heart disease, cerebrovascular disease, and peripheral arterial disease (PAD). In the population of people living with DM, PAD is characterised by multi-level atherosclerotic lesions as well as greater involvement of the arteries below the knee. DM is also a factor that significantly increases the risk of lower limb amputation. Percutaneous balloon angioplasty with or without stent implantation is an important method of the treatment for atherosclerotic cardiovascular diseases, but restenosis is a factor limiting its long-term effectiveness. The pathogenesis of atherosclerosis in the course of DM differs slightly from that in the general population. In the population of people living with DM, more attention is drawn to such factors as inflammation, endothelial dysfunction, platelet dysfunction, blood rheological properties, hypercoagulability, and additional factors stimulating vascular smooth muscle cell proliferation. DM is a risk factor for restenosis. The purpose of this paper is to provide a review of the literature and to present the most important information on the current state of knowledge on mechanisms and the clinical significance of restenosis and in-stent restenosis in patients with DM, especially in association with the endovascular treatment of PAD. The role of such processes as inflammation, neointimal hyperplasia and neoatherosclerosis, allergy, resistance to antimitotic drugs used for coating stents and balloons, genetic factors, and technical and mechanical factors are discussed. The information on restenosis collected in this publication may be helpful in planning further research in this field, which may contribute to the formulation of more and more precise recommendations for the clinical practice.
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Affiliation(s)
- Grzegorz K. Jakubiak
- Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland; (G.K.J.); (G.C.)
| | - Natalia Pawlas
- Department of Pharmacology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Jordana 38 St., 41-800 Zabrze, Poland;
| | - Grzegorz Cieślar
- Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland; (G.K.J.); (G.C.)
| | - Agata Stanek
- Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland; (G.K.J.); (G.C.)
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Yan Z, Du L, Liu Q, Zhou L, Hu Z. Remote limb ischaemic conditioning produces cardioprotection in rats with testicular ischaemia-reperfusion injury. Exp Physiol 2021; 106:2223-2234. [PMID: 34487401 DOI: 10.1113/ep089289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 08/31/2021] [Indexed: 02/05/2023]
Abstract
NEW FINDINGS What is the central question of this study? Can remote limb ischaemic conditioning produce cardioprotection in rats with testicular ischaemia-reperfusion injury? What is the main finding and its importance? Testicular ischaemia-reperfusion (TI/R)-injured rats were predisposed to myocardial reperfusion-induced atrioventricular block. Remote limb ischaemia preconditioning and postconditioning protected TI/R hearts against ischaemia-provoked ventricular arrhythmia and ultimately reduced the incidence of sudden cardiac death, with a possible role of c-Jun N-terminal kinase inhibition and connexin 43 activation. ABSTRACT Remote ischaemic conditioning can protect hearts against arrhythmia. Testicular ischaemia-reperfusion (TI/R) injury is associated with electrocardiographic abnormalities. We investigated the effect of remote limb ischaemia preconditioning (RIPre) and postconditioning (RIPost) on arrhythmogenesis in TI/R rats, and determined the potential role of c-Jun N-terminal kinase (JNK)/connexin 43 (Cx43) signalling. Rats were randomized to sham-operated, control, TI/R, RIPre and RIPost groups. TI/R rats were more predisposed to myocardial reperfusion-induced atrioventricular block (AVB). RIPre and RIPost reduced the incidence of sudden cardiac death (SCD) or AVB, and duration of ventricular tachyarrhythmias during myocardial reperfusion. RIPre and RIPost decreased myocardial I/R-induced phosphorylation level of JNK, while preserving myocardial Cx43 expression in TI/R rats. Taken together, TI/R rats were predisposed to myocardial reperfusion-induced AVB. RIPre and RIPost protected TI/R hearts against ischaemia-provoked ventricular arrhythmia and ultimately reduced the incidence of SCD by suppressing JNK activation and restoring Cx43 expression.
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Affiliation(s)
- Zhibing Yan
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Lei Du
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Quanhua Liu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Leng Zhou
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhaoyang Hu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
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Wang JD, Shao Y, Liu D, Liu NY, Zhu DY. Rictor/mTORC2 involves mitochondrial function in ES cells derived cardiomyocytes via mitochondrial Connexin 43. Acta Pharmacol Sin 2021; 42:1790-1797. [PMID: 33547375 PMCID: PMC8563760 DOI: 10.1038/s41401-020-00591-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 09/27/2020] [Indexed: 12/11/2022]
Abstract
Rictor is a key component of the mammalian target of rapamycin complex 2 (mTORC2) and is required for Akt phosphorylation (Ser473). Our previous study shows that knockdown of Rictor prevents cardiomyocyte differentiation from mouse embryonic stem (ES) cells and induces abnormal electrophysiology of ES cell-derived cardiomyocytes (ESC-CMs). Besides, knockdown of Rictor causes down-expression of connexin 43 (Cx43), the predominant gap junction protein, that is located in both the sarcolemma and mitochondria in cardiomyocytes. Mitochondrial Cx43 (mtCx43) plays a crucial role in mitochondrial function. In this study, we used the model of cardiomyocyte differentiation from mouse ES cells to elucidate the mechanisms for the mitochondrial damage in ESC-CMs after knockdown of Rictor. We showed swollen and ruptured mitochondria were observed after knockdown of Rictor under transmission electron microscope. ATP production and mitochondrial transmembrane potential were significantly decreased in Rictor-knockdown cells. Furthermore, knockdown of Rictor inhibited the activities of mitochondrial respiratory chain complex. The above-mentioned changes were linked to inhibiting the translocation of Cx43 into mitochondria by knockdown of Rictor. We revealed that knockdown of Rictor inactivated the mTOR/Akt signalling pathway and subsequently decreased HDAC6 expression, resulted in Hsp90 hyper-acetylation caused by HDAC6 inhibition, thus, inhibited the formation of Hsp90-Cx43-TOM20 complex. In conclusion, the mitochondrial Cx43 participates in shRNA-Rictor-induced mitochondrial function damage in the ESC-CMs.
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Pecoraro M, Marzocco S, Popolo A. Diazoxide Needs Mitochondrial Connexin43 to Exert Its Cytoprotective Effect in a Cellular Model of CoCl 2-Induced Hypoxia. Int J Mol Sci 2021; 22:ijms222111599. [PMID: 34769027 PMCID: PMC8583808 DOI: 10.3390/ijms222111599] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/22/2021] [Accepted: 10/24/2021] [Indexed: 02/07/2023] Open
Abstract
Hypoxia is the leading cause of death in cardiomyocytes. Cells respond to oxygen deprivation by activating cytoprotective programs, such as mitochondrial connexin43 (mCx43) overexpression and the opening of mitochondrial KATP channels, aimed to reduce mitochondrial dysfunction. In this study we used an in vitro model of CoCl2-induced hypoxia to demonstrate that mCx43 and KATP channels cooperate to induce cytoprotection. CoCl2 administration induces apoptosis in H9c2 cells by increasing mitochondrial ROS production, intracellular and mitochondrial calcium overload and by inducing mitochondrial membrane depolarization. Diazoxide, an opener of KATP channels, reduces all these deleterious effects of CoCl2 only in the presence of mCx43. In fact, our results demonstrate that in the presence of radicicol, an inhibitor of Cx43 translocation to mitochondria, the cytoprotective effects of diazoxide disappear. In conclusion, these data confirm that there exists a close functional link between mCx43 and KATP channels.
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Querio G, Antoniotti S, Geddo F, Tullio F, Penna C, Pagliaro P, Gallo MP. Ischemic heart disease and cardioprotection: Focus on estrogenic hormonal setting and microvascular health. Vascul Pharmacol 2021; 141:106921. [PMID: 34592428 DOI: 10.1016/j.vph.2021.106921] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/14/2021] [Accepted: 09/23/2021] [Indexed: 12/12/2022]
Abstract
Ischemic Heart Disease (IHD) is a clinical condition characterized by insufficient blood flow to the cardiac tissue, and the consequent inappropriate oxygen and nutrients supply and metabolic waste removal in the heart. In the last decade a broad scientific literature has underlined the distinct mechanism of onset and the peculiar progress of IHD between female and male patients, highlighting the estrogenic hormonal setting as a key factor of these sex-dependent divergences. In particular, estrogen-activated cardioprotective pathways exert a pivotal role for the microvascular health, and their impairment, both physiologically and pathologically driven, predispose to vascular dysfunctions. Aim of this review is to summarize the current knowledge on the estrogen receptors localization and function in the cardiovascular system, particularly focusing on sex-dependent differences in microvascular vs macrovascular dysfunction and on the experimental models that allowed the researchers to reach the current findings and sketching the leading estrogen-mediated cardioprotective mechanisms.
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Affiliation(s)
- Giulia Querio
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | - Susanna Antoniotti
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | - Federica Geddo
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | - Francesca Tullio
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Claudia Penna
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
| | - Maria Pia Gallo
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.
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Zhao F, Zou MH. Role of the Mitochondrial Protein Import Machinery and Protein Processing in Heart Disease. Front Cardiovasc Med 2021; 8:749756. [PMID: 34651031 PMCID: PMC8505727 DOI: 10.3389/fcvm.2021.749756] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022] Open
Abstract
Mitochondria are essential organelles for cellular energy production, metabolic homeostasis, calcium homeostasis, cell proliferation, and apoptosis. About 99% of mammalian mitochondrial proteins are encoded by the nuclear genome, synthesized as precursors in the cytosol, and imported into mitochondria by mitochondrial protein import machinery. Mitochondrial protein import systems function not only as independent units for protein translocation, but also are deeply integrated into a functional network of mitochondrial bioenergetics, protein quality control, mitochondrial dynamics and morphology, and interaction with other organelles. Mitochondrial protein import deficiency is linked to various diseases, including cardiovascular disease. In this review, we describe an emerging class of protein or genetic variations of components of the mitochondrial import machinery involved in heart disease. The major protein import pathways, including the presequence pathway (TIM23 pathway), the carrier pathway (TIM22 pathway), and the mitochondrial intermembrane space import and assembly machinery, related translocases, proteinases, and chaperones, are discussed here. This review highlights the importance of mitochondrial import machinery in heart disease, which deserves considerable attention, and further studies are urgently needed. Ultimately, this knowledge may be critical for the development of therapeutic strategies in heart disease.
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Affiliation(s)
| | - Ming-Hui Zou
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, United States
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Jindal S, Chockalingam S, Ghosh SS, Packirisamy G. Connexin and gap junctions: perspectives from biology to nanotechnology based therapeutics. Transl Res 2021; 235:144-167. [PMID: 33582245 DOI: 10.1016/j.trsl.2021.02.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 01/10/2021] [Accepted: 02/09/2021] [Indexed: 12/11/2022]
Abstract
The concept of gap junctions and their role in intercellular communication has been known for around 50 years. Considerable progress has been made in understanding the fundamental biology of connexins in mediating gap junction intercellular communication (GJIC) and their role in various cellular processes including pathological conditions. However, this understanding has not led to development of advanced therapeutics utilizing GJIC. Inadequacies in strategies that target specific connexin protein in the affected tissue, with minimal or no collateral damage, are the primary reason for the lack of development of efficient therapeutic models. Herein, nanotechnology has a role to play, giving plenty of scope to circumvent these problems and develop more efficient connexin based therapeutics. AsODN, antisense oligodeoxynucleotides; BMPs, bone morphogenetic proteins; BMSCs, bone marrow stem cells; BG, bioglass; Cx, Connexin; CxRE, connexin-responsive elements; CoCr NPs, cobalt-chromium nanoparticles; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; cAMP, cyclic adenosine monophosphate; ERK1/2, extracellular signal-regulated kinase 1/2; EMT, epithelial-mesenchymal transition; EPA, eicosapentaenoic acids; FGFR1, fibroblast growth factor receptor 1; FRAP, fluorescence recovery after photobleaching; 5-FU, 5-fluorouracil; GJ, gap junction; GJIC, gap junctional intercellular communication; HGPRTase, hypoxanthine phosphoribosyltransferase; HSV-TK, herpes virus thymidine kinase; HSA, human serum albumin; HA, hyaluronic acid; HDAC, histone deacetylase; IRI, ischemia reperfusion injury; IL-6, interleukin-6; IL-8, interleukin-8; IONPs, iron-oxide nanoparticles; JNK, c-Jun N-terminal kinase; LAMP, local activation of molecular fluorescent probe; MSCs, mesenchymal stem cells; MMP, matrix metalloproteinase; MI, myocardial infarction; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; NO, nitric oxide; PKC, protein kinase C; QDs, quantum dots; ROI, region of interest; RGO, reduced graphene oxide; siRNA, small interfering RNA; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor-α; UCN, upconversion nanoparticles; VEGF, vascular endothelial growth factor. In this review, we discuss briefly the role of connexins and gap junctions in various physiological and pathological processes, with special emphasis on cancer. We further discuss the application of nanotechnology and tissue engineering in developing treatments for various connexin based disorders.
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Affiliation(s)
- Shlok Jindal
- Nanobiotechnology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India
| | - S Chockalingam
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, Telangana, India
| | - Siddhartha Sankar Ghosh
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Gopinath Packirisamy
- Nanobiotechnology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India; Centre for Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India.
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50
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Herradón E, González C, González A, Uranga JA, López-Miranda V. Cardiovascular Toxicity Induced by Chronic Vincristine Treatment. Front Pharmacol 2021; 12:692970. [PMID: 34366848 PMCID: PMC8333869 DOI: 10.3389/fphar.2021.692970] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/23/2021] [Indexed: 12/30/2022] Open
Abstract
Vincristine is an effective anticancer agent for treating leukemias, lymphomas, and other solid tumors. Vincristine's better-known severe side effects include bone marrow depression, hyponatremia, peripheral neuropathy, and gastrointestinal distress. In recent years, cardiovascular damage also has been described during vincristine treatments. However, the vascular toxicity induced by vincristine is little studied. The aim of the present is to evaluate whether these alterations remain after the suspension of chemotherapy treatment (sequelae) and the possible mechanisms involved in this vascular damage. Adult male Wistar rats were used. The animals were divided into four treatment groups: two groups of saline (0.9% NaCl; saline, sequelae saline) and two groups of vincristine (100 μg/kg; vincristine, sequelae vincristine). Saline or vincristine was administered intraperitoneally in two cycles of 5 days each, leaving a rest period between cycles of 2 days. The final cumulative vincristine dose administered was 1 mg/kg. Sequelae groups correspond to 2 weeks after stopping treatment with the antitumor agent. At the end of the different experimental protocols, cardiac and vascular functions were analyzed. Alterations in the expression of different proteins in the cardiovascular tissues were also investigated. Chronic treatment with vincristine did not produce significant changes in basal cardiac function but provoked significant endothelial dysfunction in the aorta and a significant decrease in the mesenteric contractile function. These cardiovascular functional alterations disappeared 2 weeks after the suspension of chemotherapy treatment. Vincristine treatment caused a significant increase in the expression of tumor necrosis factor-alpha (TNFα), endothelial and inducible nitric oxide synthases (eNOS and iNOS), and connexin 43 in cardiac tissue. In the aorta, the chronic treatment with vincristine caused a slight non-significant increase in TNFα expression, a significant increase in eNOS and iNOS, and a significant decrease in connexin 43. After 2 weeks of vincristine treatment (sequelae group), the expression of TNFα increased and eNOS and iNOS expressions disappeared, but a significant decrease in the expression of connexin 43 was still observed in the aorta. In mesenteric arteries, similar data to those found in the aorta were observed. In conclusion, chronic treatment with vincristine causes functional alterations in the vascular function of both conductance and resistance vessels and changes in the expressions of TNFα, eNOS, iNOS, and connexin 43 in cardiovascular tissues, implicating direct toxicity during its treatment. These functional alterations are transitory and disappear after the suspension of its treatment.
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Affiliation(s)
- Esperanza Herradón
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.,Unidad Asociada al Instituto de Química Medica (IQM) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Spain.,High Performance Research Group in Experimental Pharmacology (Pharmakom-URJC), URJC, Alcorcón, Spain
| | - Cristina González
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.,Unidad Asociada al Instituto de Química Medica (IQM) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Spain
| | - Antonio González
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.,Unidad Asociada al Instituto de Química Medica (IQM) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Spain.,High Performance Research Group in Experimental Pharmacology (Pharmakom-URJC), URJC, Alcorcón, Spain
| | - Jose Antonio Uranga
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.,High Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), URJC, Alcorcón, Spain
| | - Visitación López-Miranda
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.,Unidad Asociada al Instituto de Química Medica (IQM) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Spain.,High Performance Research Group in Experimental Pharmacology (Pharmakom-URJC), URJC, Alcorcón, Spain
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