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Zahir A, Okorie PA, Nwobasi VN, David EI, Nwankwegu RO, Azi F. Harnessing Microbial Signal Transduction Systems in Natural and Synthetic Consortia for Biotechnological Applications. Biotechnol Appl Biochem 2024. [PMID: 39740178 DOI: 10.1002/bab.2707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 11/24/2024] [Indexed: 01/02/2025]
Abstract
Signal transduction is crucial for communication and cellular response in microbial communities. Consortia rely on it for effective communication, responding to changing environmental conditions, establishing community structures, and performing collective behaviors. Microbial signal transduction can be through quorum sensing (QS), two-component signal transduction systems, biofilm formation, nutrient sensing, chemotaxis, horizontal gene transfer stress response, and so forth. The consortium uses small signaling molecules in QS to regulate gene expression and coordinate intercellular communication and behaviors. Biofilm formation allows cells to adhere and aggregate, promoting species interactions and environmental stress resistance. Chemotaxis enables directional movement toward or away from chemical gradients, promoting efficient resource utilization and community organization within the consortium. In recent years, synthetic microbial consortia have gained attention for their potential applications in biotechnology and bioremediation. Understanding signal transduction in natural and synthetic microbial consortia is important for gaining insights into community dynamics, evolution, and ecological function. It can provide strategies for biotechnological innovation for enhancing biosensors, biodegradation, bioenergy efficiency, and waste reduction. This review provides compelling insight that will advance our understanding of microbial signal transduction dynamics and its role in orchestrating microbial interactions, which facilitate coordination, cooperation, gene expression, resource allocation, and trigger specific responses that determine community success.
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Affiliation(s)
- Ahmadullah Zahir
- Department of Food Science and Technology, Faculty of Veterinary Sciences, Afghanistan National Agricultural Sciences & Technology University, Kandahar, Afghanistan
| | - Peter A Okorie
- Department of Food Science & Technology, Ebonyi State University EBSU, Abakaliki, Nigeria
| | - Veronica N Nwobasi
- Department of Food Science & Technology, Ebonyi State University EBSU, Abakaliki, Nigeria
| | - Esther I David
- Department of Home Economics, Ebonyi State University EBSU, Abakaliki, Nigeria
| | - Rita O Nwankwegu
- Department of Food Science & Technology, Ebonyi State University EBSU, Abakaliki, Nigeria
| | - Fidelis Azi
- Department of Chemical Engineering, Guangdong Technion-Israel Institute of Technology (GTIIT), Shantou, Guangdong, China
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Subedi R, Soulat A, Rauf Butt S, Mohan A, Danish Butt M, Arwani S, Ahmed G, Majumder K, Mohan Lal P, Kumar V, Tejwaney U, Ram N, Kumar S. Exploring the association between atrial fibrillation and celiac disease: a comprehensive review. Ann Med Surg (Lond) 2024; 86:7155-7163. [PMID: 39649916 PMCID: PMC11623827 DOI: 10.1097/ms9.0000000000002259] [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] [Received: 06/24/2023] [Accepted: 05/10/2024] [Indexed: 12/11/2024] Open
Abstract
Objective This paper aims to provide a comprehensive overview of the pathophysiology of atrial fibrillation (AF) and celiac disease (CD) individually while also exploring the emerging evidence of a potential association between the two conditions. Methods The pathophysiology of AF, the most prevalent arrhythmia globally, and CD, an autoimmune condition triggered by gluten consumption, is examined. Genetic, structural, electrophysiological, and inflammatory factors contributing to their development are explored. Results AF involves irregular atrial activity leading to electrical and structural remodeling of the atrium. CD is characterized by an immune response to gluten, primarily associated with HLA-DQ2 and HLA-DQ8 genetic mutations, resulting in damage to intestinal tissue. Emerging research suggests a link between AF and CD, possibly mediated through inflammation, fibrosis, and electromechanical delays in the atrium. Conclusion Understanding the association between AF and CD carries significant clinical implications. Recognition of this relationship can assist in identifying individuals at higher risk for AF and inform proactive management strategies. Additionally, it underscores the importance of comprehensive care for CD patients, considering potential cardiac implications. Further research is warranted to elucidate precise mechanisms and explore potential therapeutic interventions targeting common pathways, opening avenues for enhanced patient care and future investigations.
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Affiliation(s)
- Rasish Subedi
- Universal College of Medical Sciences, Siddharthanagar
| | | | | | | | | | | | | | | | | | | | | | - Nanik Ram
- Aga Khan University Hospital, Karachi
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Deissler PM, Tran KL, Falk V, Pieske B, Grubitzsch H, Primessnig U, Heinzel FR. Functional reserve and contractile phenotype of atrial myocardium from patients with atrial remodeling without and with atrial fibrillation. Am J Physiol Heart Circ Physiol 2023; 325:H729-H738. [PMID: 37594484 DOI: 10.1152/ajpheart.00355.2023] [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: 06/19/2023] [Revised: 07/26/2023] [Accepted: 08/04/2023] [Indexed: 08/19/2023]
Abstract
Atrial contractility and functional reserve in atrial remodeling (AR) without (AR/-AF) or with atrial fibrillation (AR/+AF) are not well characterized. In this study, functional measurements were performed in right atrial muscle strips (n = 71) obtained from patients (N = 22) undergoing routine cardiac surgery with either no AR [left atrial (LA) diameter < 40 mm and no history of AF (hAF)], AR/-AF (LA diameter ≥ 40 mm, no hAF), or AR/+AF (hAF and LA diameter ≥ 40 mm or LAEF < 45%). AR/-AF and AR/+AF were associated with a prolongation of half-time-to-peak (HTTP, P < 0.001) and time-to-peak (TTP) contraction (P < 0.01) when compared with no AR. This effect was seen at baseline and during β-adrenergic stimulation with isoproterenol (Iso). Early relaxation assessed by half-relaxation time (HRT) was prolonged in AR/-AF (P = 0.03) but not in AR/+AF when compared with no AR at baseline, but this delay in relaxation in AR/-AF was attenuated with Iso. Late relaxation (τ) did not differ between AR/-AF and no AR but was consistently shorter in AR/+AF than no AR before (P = 0.04) and during Iso (P = 0.01), indicating accelerated late relaxation in AR/+AF. Relative force increase during Iso was higher (P = 0.01) and more dispersed (P = 0.047) in patients with AR/+AF. Relative adrenergic response was unaltered in the myocardium of patients with AR/-AF and AR/+AF. In conclusion, AR/-AF and AR/+AF are associated with changes in myocardial inotropic reserve and contractility. The changes are particularly pronounced in patients with AR/+AF, suggesting that the progression from AR/-AF to AR/+AF is associated with progressive alterations in atrial function that may contribute to arrhythmogenesis.NEW & NOTEWORTHY Mechanical alterations in atrial remodeling without (AR/-AF) and with atrial fibrillation (AR/+AF) have not been studied in detail in human atrial tissue preparations. To our knowledge, this is the first study to compare the mechanical phenotype and inotropic reserve in human atrial myocardial preparations from patients with no atrial remodeling, AR/-AF, and AR/+AF. We identify specific patterns of contractile dysfunction and heterogeneity for both, AR/-AF and AR/+AF, indicating the progression of atrial disease.
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Affiliation(s)
- Peter M Deissler
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Khai Liem Tran
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Volkmar Falk
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
| | | | - Herko Grubitzsch
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
| | - Uwe Primessnig
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Frank R Heinzel
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
- 2. Medizinische Klinik-Kardiologie, Angiologie, Intensivmedizin, Städtisches Klinikum Dresden, Dresden, Germany
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Atzemian N, Dovrolis N, Ragia G, Portokallidou K, Kolios G, Manolopoulos VG. Beyond the Rhythm: In Silico Identification of Key Genes and Therapeutic Targets in Atrial Fibrillation. Biomedicines 2023; 11:2632. [PMID: 37893006 PMCID: PMC10604372 DOI: 10.3390/biomedicines11102632] [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: 07/31/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/29/2023] Open
Abstract
Atrial fibrillation (AF) is a prevalent cardiac arrhythmia worldwide and is characterized by a high risk of thromboembolism, ischemic stroke, and fatality. The precise molecular mechanisms of AF pathogenesis remain unclear. The purpose of this study was to use bioinformatics tools to identify novel key genes in AF, provide deeper insights into the molecular pathogenesis of AF, and uncover potential therapeutic targets. Four publicly available raw RNA-Seq datasets obtained through the ENA Browser, as well as proteomic analysis results, both derived from atrial tissues, were used in this analysis. Differential gene expression analysis was performed and cross-validated with proteomics results to identify common genes/proteins between them. A functional enrichment pathway analysis was performed. Cross-validation analysis revealed five differentially expressed genes, namely FGL2, IGFBP5, NNMT, PLA2G2A, and TNC, in patients with AF compared with those with sinus rhythm (SR). These genes play crucial roles in various cardiovascular functions and may be part of the molecular signature of AF. Furthermore, functional enrichment analysis revealed several pathways related to the extracellular matrix, inflammation, and structural remodeling. This study highlighted five key genes that constitute promising candidates for further experimental exploration as biomarkers as well as therapeutic targets for AF.
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Affiliation(s)
- Natalia Atzemian
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (N.A.); (G.R.); (K.P.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Nikolas Dovrolis
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (N.A.); (G.R.); (K.P.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Georgia Ragia
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (N.A.); (G.R.); (K.P.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Konstantina Portokallidou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (N.A.); (G.R.); (K.P.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - George Kolios
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (N.A.); (G.R.); (K.P.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Vangelis G. Manolopoulos
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (N.A.); (G.R.); (K.P.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
- Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, 68100 Alexandroupolis, Greece
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Yang L, Chen Y, Huang W. Hub Genes Identification, Small Molecule Compounds Prediction for Atrial Fibrillation and Diagnostic Model Construction Based on XGBoost Algorithm. Front Cardiovasc Med 2022; 9:920399. [PMID: 35911532 PMCID: PMC9329605 DOI: 10.3389/fcvm.2022.920399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundAtrial fibrillation (AF) is the most common sustained cardiac arrhythmia and engenders significant global health care burden. The underlying mechanisms of AF is remained to be revealed and current treatment options for AF have limitations. Besides, a detection system can help identify those at risk of developing AF and will enable personalized management.Materials and MethodsIn this study, we utilized the robust rank aggregation method to integrate six AF microarray datasets from the Gene Expression Omnibus database, and identified a set of differentially expressed genes between patients with AF and controls. Potential compounds were identified by mining the Connectivity Map database. Functional modules and closely-interacted clusters were identified using weighted gene co-expression network analysis and protein–protein interaction network, respectively. The overlapped hub genes were further filtered. Subsequent analyses were performed to analyze the function, biological features, and regulatory networks. Moreover, a reliable Machine Learning-based diagnostic model was constructed and visualized to clarify the diagnostic features of these genes.ResultsA total of 156 upregulated and 34 downregulated genes were identified, some of which had not been previously investigated. We showed that mitogen-activated protein kinase and epidermal growth factor receptor inhibitors were likely to mitigate AF based on Connectivity Map analysis. Four genes, including CXCL12, LTBP1, LOXL1, and IGFBP3, were identified as hub genes. CXCL12 was shown to play an important role in regulation of local inflammatory response and immune cell infiltration. Regulation of CXCL12 expression in AF was analyzed by constructing a transcription factor-miRNA-mRNA network. The Machine Learning-based diagnostic model generated in this study showed good efficacy and reliability.ConclusionKey genes involving in the pathogenesis of AF and potential therapeutic compounds for AF were identified. The biological features of CXCL12 in AF were investigated using integrative bioinformatics tools. The results suggested that CXCL12 might be a biomarker that could be used for distinguishing subsets of AF, and indicated that CXCL12 might be an important intermediate in the development of AF. A reliable Machine Learning-based diagnostic model was constructed. Our work improved understanding of the mechanisms of AF predisposition and progression, and identified potential therapeutic avenues for treatment of AF.
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Goette A, Lendeckel U. Atrial Cardiomyopathy: Pathophysiology and Clinical Consequences. Cells 2021; 10:cells10102605. [PMID: 34685585 PMCID: PMC8533786 DOI: 10.3390/cells10102605] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 09/26/2021] [Indexed: 12/18/2022] Open
Abstract
Around the world there are 33.5 million patients suffering from atrial fibrillation (AF) with an annual increase of 5 million cases. Most AF patients have an established form of an atrial cardiomyopathy. The concept of atrial cardiomyopathy was introduced in 2016. Thus, therapy of underlying diseases and atrial tissue changes appear as a cornerstone of AF therapy. Furthermore, therapy or prevention of atrial endocardial changes has the potential to reduce atrial thrombogenesis and thereby cerebral stroke. The present manuscript will summarize the underlying pathophysiology and remodeling processes observed in the development of an atrial cardiomyopathy, thrombogenesis, and atrial fibrillation. In particular, the impact of oxidative stress, inflammation, diabetes, and obesity will be addressed.
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Affiliation(s)
- Andreas Goette
- Department of Cardiology and Intensive Care Medicine, St. Vincenz Hospital, 33098 Paderborn, Germany
- MAESTRIA Consortium/AFNET, 48149 Münster, Germany
- Correspondence:
| | - Uwe Lendeckel
- Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, 17475 Greifswald, Germany;
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Campbell H, Aguilar-Sanchez Y, Quick AP, Dobrev D, Wehrens XHT. SPEG: a key regulator of cardiac calcium homeostasis. Cardiovasc Res 2020; 117:2175-2185. [PMID: 33067609 DOI: 10.1093/cvr/cvaa290] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/15/2020] [Accepted: 10/02/2020] [Indexed: 12/27/2022] Open
Abstract
Proper cardiac Ca2+ homeostasis is essential for normal excitation-contraction coupling. Perturbations in cardiac Ca2+ handling through altered kinase activity has been implicated in altered cardiac contractility and arrhythmogenesis. Thus, a better understanding of cardiac Ca2+ handling regulation is vital for a better understanding of various human disease processes. 'Striated muscle preferentially expressed protein kinase' (SPEG) is a member of the myosin light chain kinase family that is key for normal cardiac function. Work within the last 5 years has revealed that SPEG has a crucial role in maintaining normal cardiac Ca2+ handling through maintenance of transverse tubule formation and phosphorylation of junctional membrane complex proteins. Additionally, SPEG has been causally impacted in human genetic diseases such as centronuclear myopathy and dilated cardiomyopathy as well as in common acquired cardiovascular disease such as heart failure and atrial fibrillation. Given the rapidly emerging role of SPEG as a key cardiac Ca2+ regulator, we here present this review in order to summarize recent findings regarding the mechanisms of SPEG regulation of cardiac excitation-contraction coupling in both physiology and human disease. A better understanding of the roles of SPEG will be important for a more complete comprehension of cardiac Ca2+ regulation in physiology and disease.
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Affiliation(s)
- Hannah Campbell
- Cardiovascular Research Institute, Baylor College of Medicine, One Baylor Plaza, BCM335, Houston, TX 77030, USA.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.,Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yuriana Aguilar-Sanchez
- Cardiovascular Research Institute, Baylor College of Medicine, One Baylor Plaza, BCM335, Houston, TX 77030, USA.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ann P Quick
- Cardiovascular Research Institute, Baylor College of Medicine, One Baylor Plaza, BCM335, Houston, TX 77030, USA.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Dobromir Dobrev
- Cardiovascular Research Institute, Baylor College of Medicine, One Baylor Plaza, BCM335, Houston, TX 77030, USA.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.,Institute of Pharmacology, University Duisburg-Essen, Essen, Germany
| | - Xander H T Wehrens
- Cardiovascular Research Institute, Baylor College of Medicine, One Baylor Plaza, BCM335, Houston, TX 77030, USA.,Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.,Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.,Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.,Center for Space Medicine, Baylor College of Medicine, Houston, TX 77030, USA
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8
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Guo WH, Wang X, Shang MS, Chen Z, Guo Q, Li L, Wang HY, Yu RH, Ma CS. Crosstalk between PKC and MAPK pathway activation in cardiac fibroblasts in a rat model of atrial fibrillation. Biotechnol Lett 2020; 42:1219-1227. [PMID: 32095918 DOI: 10.1007/s10529-020-02843-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 02/19/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Atrial fibrillation (AF) is the most frequent form of cardiac arrhythmia and major cause of cardiac ischemia. Defective calcium homeostasis due to anomalous expression of ryanodine receptor type 2 (RyR2) or its hyperactivation by phosphorylation by serine threonine kinases has been implicated as a central mechanism of AF pathogenesis. Given the role of protein kinase C (PKC) isoforms in cardiac function we investigated role of PKC in AF using a rat model. RESULTS PMA induced global increase in protein synthesis in cardiac fibroblasts isolated from AF rats, but not healthy controls, and the increase was inhibited by PKC inhibition. PMA mediated activation of both PKC and ERK and either inhibition of PKC by Go6983 or ERK by the MEK inhibitor Trametinib attenuated both P-ERK and P-PKC in both cardiac fibroblasts isolated from AF rats or from healthy rats but transduced with PKC-delta. The PKC and ERK mediated induction of global protein synthesis was found to be mediated by increased phosphorylation of the ribosomal protein S6. CONCLUSION Our findings provide a foundation for future testing of PKC and MEK inhibitors to treat AF in pre-clinical models. It also needs to be determined if PKC and MAPK pathway activation is functioning via RyR2 or some yet undefined substrates.
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Affiliation(s)
- Wei-Hua Guo
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xian Wang
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Mei-Sheng Shang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, No.2, Anzhen Road, Chaoyang District, Beijing, 100029, China
| | - Zhe Chen
- Department of Cardiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100005, China
| | - Qi Guo
- Department of Cardiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100005, China
| | - Li Li
- Department of Cardiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100005, China
| | - Hai-Ying Wang
- Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Rong-Hui Yu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, No.2, Anzhen Road, Chaoyang District, Beijing, 100029, China
| | - Chang-Sheng Ma
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, No.2, Anzhen Road, Chaoyang District, Beijing, 100029, China.
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Wang X, Shangguan W, Li G. Angiotensin-(1-7) prevents atrial tachycardia induced-heat shock protein 27 expression. J Electrocardiol 2017; 51:117-120. [PMID: 29056233 DOI: 10.1016/j.jelectrocard.2017.08.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Indexed: 11/29/2022]
Abstract
OBJECTIVE We aimed to investigate the effects of angiotensin-(1-7) [Ang-(1-7)] on heat-shock protein 27 (HSP27) in a canine model of induced tachycardia. METHODS Eighteen dogs were randomized into three equal treatment groups: sham, pacing and pacing+Ang-(1-7) group. The dogs in the last two groups were subjected to 2weeks of rapid atrial pacing (500bpm). The effects of Ang-(1-7) on HSP27 were assessed by real-time polymerase chain reaction and western blot. RESULTS The expression levels of atrial HSP27 mRNA and protein were significantly (P<0.05) higher for the pacing group than the sham group and significantly (P<0.05) lower for the pacing+Ang-(1-7) group than the pacing group. There was no significant difference between the HSP27 expression levels in the right and left atria among all three groups. CONCLUSIONS Our findings suggest that the overexpression of HSP27 may possibly be occurring as an adaptive response that allows atrial tissues to cope with rapid atrial pacing, and an inhibiting effect of Ang-(1-7) on atrial remodeling may be one of the mechanisms responsible for the attenuation of HSP27 up-regulation induced by rapid pacing.
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Affiliation(s)
- Xuewen Wang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Wenfeng Shangguan
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Guangping Li
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China.
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Grandi E, Maleckar MM. Anti-arrhythmic strategies for atrial fibrillation: The role of computational modeling in discovery, development, and optimization. Pharmacol Ther 2016; 168:126-142. [PMID: 27612549 DOI: 10.1016/j.pharmthera.2016.09.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with increased risk of cerebrovascular stroke, and with several other pathologies, including heart failure. Current therapies for AF are targeted at reducing risk of stroke (anticoagulation) and tachycardia-induced cardiomyopathy (rate or rhythm control). Rate control, typically achieved by atrioventricular nodal blocking drugs, is often insufficient to alleviate symptoms. Rhythm control approaches include antiarrhythmic drugs, electrical cardioversion, and ablation strategies. Here, we offer several examples of how computational modeling can provide a quantitative framework for integrating multiscale data to: (a) gain insight into multiscale mechanisms of AF; (b) identify and test pharmacological and electrical therapy and interventions; and (c) support clinical decisions. We review how modeling approaches have evolved and contributed to the research pipeline and preclinical development and discuss future directions and challenges in the field.
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Affiliation(s)
- Eleonora Grandi
- Department of Pharmacology, University of California Davis, Davis, USA.
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11
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Raiten JM, Ghadimi K, Augoustides JGT, Ramakrishna H, Patel PA, Weiss SJ, Gutsche JT. Atrial fibrillation after cardiac surgery: clinical update on mechanisms and prophylactic strategies. J Cardiothorac Vasc Anesth 2016; 29:806-16. [PMID: 26009291 DOI: 10.1053/j.jvca.2015.01.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Indexed: 11/11/2022]
Affiliation(s)
- Jesse M Raiten
- Cardiovascular Critical Care Section, Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Kamrouz Ghadimi
- Division of CT Anesthesiology and Critical Care Medicine, Department of Anesthesiology, School of Medicine, Duke University, Durham, NC
| | - John G T Augoustides
- Cardiovascular and Thoracic Section, Departmsent of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
| | | | - Prakash A Patel
- Cardiovascular and Thoracic Section, Departmsent of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Stuart J Weiss
- Cardiovascular and Thoracic Section, Departmsent of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jacob T Gutsche
- Cardiovascular and Thoracic Section, Departmsent of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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12
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Verdejo HE, Becerra E, Zalaquet R, Del Campo A, Garcia L, Troncoso R, Chiong M, Marin A, Castro PF, Lavandero S, Gabrielli L, Corbalán R. Atrial Function Assessed by Speckle Tracking Echocardiography Is a Good Predictor of Postoperative Atrial Fibrillation in Elderly Patients. Echocardiography 2015; 33:242-8. [PMID: 26394799 DOI: 10.1111/echo.13059] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE Advanced age is an independent predictor of postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass surgery. We evaluated whether left atrial (LA) dysfunction assessed by strain contributes to identifying elderly patients prone to POAF. METHODS Case-control study of 70 subjects undergoing coronary artery bypass surgery. Clinical and laboratory characteristics were recorded at baseline and 72 hours after surgery. Echocardiography was performed during the preoperative period; LA dimensions and deformation by strain (systolic wave [LASs]) as well as strain rate (systolic wave [LASRs] and atrial contraction wave [LASRa]) were assessed. RESULTS Postoperative atrial fibrillation occurred in 38.5% of patients within the first 72 hours after surgery (28.5% of the younger vs. 48.6% of the older group). Baseline and postoperative inflammatory markers as well as total surgical and aortic clamp time were similar between groups. LA function was markedly impaired in subjects with POAF. Age correlated with LASs, LASRs, and LASRa. These associations remained consistent when subjects 75 years or older were considered separately. Both LASs and LASRa for patients with or without POAF, respectively, were significantly impaired in elderly subjects with POAF. Multivariate analysis provided further evidence that both LASs and age are independent predictors for POAF. CONCLUSION Age-related changes in atrial function preceding atrial dilation are evident only upon LA strain analysis. LA strain impairment is an independent predictor of POAF irrespective of age and may serve as a surrogate marker for biological processes involved in establishing the substrate for POAF.
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Affiliation(s)
- Hugo E Verdejo
- Advanced Center for Chronic Diseases, Universidad de Chile & Pontificia Universidad Catolica de Chile, Santiago, Chile.,Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Elia Becerra
- Advanced Center for Chronic Diseases, Universidad de Chile & Pontificia Universidad Catolica de Chile, Santiago, Chile.,Center for Molecular Studies of the Cell, Universidad de Chile, Santiago, Chile
| | - Ricardo Zalaquet
- Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Andrea Del Campo
- Center for Molecular Studies of the Cell, Universidad de Chile, Santiago, Chile
| | - Lorena Garcia
- Advanced Center for Chronic Diseases, Universidad de Chile & Pontificia Universidad Catolica de Chile, Santiago, Chile.,Center for Molecular Studies of the Cell, Universidad de Chile, Santiago, Chile
| | - Rodrigo Troncoso
- Advanced Center for Chronic Diseases, Universidad de Chile & Pontificia Universidad Catolica de Chile, Santiago, Chile.,Center for Molecular Studies of the Cell, Universidad de Chile, Santiago, Chile.,Nutrition Institute, Universidad de Chile, Santiago, Chile
| | - Mario Chiong
- Advanced Center for Chronic Diseases, Universidad de Chile & Pontificia Universidad Catolica de Chile, Santiago, Chile.,Center for Molecular Studies of the Cell, Universidad de Chile, Santiago, Chile
| | - Arnaldo Marin
- Department of Internal Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Pablo F Castro
- Advanced Center for Chronic Diseases, Universidad de Chile & Pontificia Universidad Catolica de Chile, Santiago, Chile.,Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases, Universidad de Chile & Pontificia Universidad Catolica de Chile, Santiago, Chile.,Center for Molecular Studies of the Cell, Universidad de Chile, Santiago, Chile.,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Luigi Gabrielli
- Advanced Center for Chronic Diseases, Universidad de Chile & Pontificia Universidad Catolica de Chile, Santiago, Chile.,Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Ramón Corbalán
- Advanced Center for Chronic Diseases, Universidad de Chile & Pontificia Universidad Catolica de Chile, Santiago, Chile.,Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
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13
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Chilukoti RK, Giese A, Malenke W, Homuth G, Bukowska A, Goette A, Felix SB, Kanaan J, Wollert HG, Evert K, Verheule S, Jais P, Hatem SN, Lendeckel U, Wolke C. Atrial fibrillation and rapid acute pacing regulate adipocyte/adipositas-related gene expression in the atria. Int J Cardiol 2015; 187:604-13. [PMID: 25863735 DOI: 10.1016/j.ijcard.2015.03.072] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Revised: 02/19/2015] [Accepted: 03/03/2015] [Indexed: 01/10/2023]
Abstract
PURPOSE Atrial fibrillation (AF) has been associated with increased volumes of epicardial fat and atrial adipocyte accumulation. Underlying mechanisms are not well understood. This study aims to identify rapid atrial pacing (RAP)/AF-dependent changes in atrial adipocyte/adipositas-related gene expression (AARE). METHODS Right atrial (RA) and adjacent epicardial adipose tissue (EAT) samples were obtained from 26 patients; 13 with AF, 13 in sinus rhythm (SR). Left atrial (LA) samples were obtained from 9 pigs (5 RAP, 4 sham-operated controls). AARE was analyzed using microarrays and RT-qPCR. The impact of diabetes/obesity on gene expression was additionally determined in RA samples (RAP ex vivo and controls) from 3 vs. 6 months old ZDF rats. RESULTS RAP in vivo of pigs resulted in substantial changes of AARE, with 66 genes being up- and 53 down-regulated on the mRNA level. Differential expression during adipocyte differentiation was confirmed using 3T3-L1 cells. In patients with AF (compared to SR), a comparable change in RA mRNA levels concerned a fraction of genes only (RETN, IGF1, HK2, PYGM, LOX, and NR4A3). RA and EAT were affected by AF to a different extent. In patients, concomitant disease contributes to AARE changes. CONCLUSIONS RAP, and to lesser extent AF, provoke significant changes in atrial AARE. In chronic AF, activation of this gene panel is very likely mediated by AF itself, AF risk factors and concomitant diseases. This may facilitate the development of an AF substrate by increasing atrial ectopic fat and fat infiltration of the atrial myocardium.
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Affiliation(s)
- R K Chilukoti
- University Medicine Greifswald, Ernst-Moritz-Arndt-University Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany
| | - A Giese
- University Medicine Greifswald, Institute of Medical Biochemistry and Molecular Biology, Greifswald, Germany
| | - W Malenke
- University Medicine Greifswald, Institute of Medical Biochemistry and Molecular Biology, Greifswald, Germany
| | - G Homuth
- University Medicine Greifswald, Ernst-Moritz-Arndt-University Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany
| | - A Bukowska
- EUTRAF Working Group: Molecular Electrophysiology, University Hospital Magdeburg, Otto-von-Guericke University, Magdeburg, Germany
| | - A Goette
- EUTRAF Working Group: Molecular Electrophysiology, University Hospital Magdeburg, Otto-von-Guericke University, Magdeburg, Germany; Cardiology and Intensive Care Medicine, St. Vincenz-Hospital, Paderborn, Germany
| | - S B Felix
- University Medicine Greifswald, Department of Cardiology, Greifswald, Germany
| | - J Kanaan
- Dr. Guth Clinics, Dept. of Cardiovascular Surgery, Karlsburg, Germany
| | - H-G Wollert
- Dr. Guth Clinics, Dept. of Cardiovascular Surgery, Karlsburg, Germany
| | - K Evert
- University Medicine Greifswald, Department of Pathology, Greifswald, Germany
| | - S Verheule
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - P Jais
- Hôpital Cardiologique du Haut Lévêque, Université Victor-Segalen Bordeaux II, Pessac, France
| | - S N Hatem
- Sorbonne Universités, UPMC University Paris 06, UMR_S 1166 I, ICAN, Paris, France
| | - U Lendeckel
- University Medicine Greifswald, Institute of Medical Biochemistry and Molecular Biology, Greifswald, Germany.
| | - C Wolke
- University Medicine Greifswald, Institute of Medical Biochemistry and Molecular Biology, Greifswald, Germany
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14
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Heart failure and atrial fibrillation: from basic science to clinical practice. Int J Mol Sci 2015; 16:3133-47. [PMID: 25647414 PMCID: PMC4346884 DOI: 10.3390/ijms16023133] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Accepted: 01/27/2015] [Indexed: 12/19/2022] Open
Abstract
Heart failure (HF) and atrial fibrillation (AF) are two growing epidemics associated with significant morbidity and mortality. They often coexist due to common risk factors and shared pathophysiological mechanisms. Patients presenting with both HF and AF have a worse prognosis and present a particular therapeutic challenge to clinicians. This review aims to appraise the common pathophysiological background, as well as the prognostic and therapeutic implications of coexistent HF and AF.
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15
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Davies L, Jin J, Shen W, Tsui H, Shi Y, Wang Y, Zhang Y, Hao G, Wu J, Chen S, Fraser JA, Dong N, Christoffels V, Ravens U, Huang CL, Zhang H, Cartwright EJ, Wang X, Lei M. Mkk4 is a negative regulator of the transforming growth factor beta 1 signaling associated with atrial remodeling and arrhythmogenesis with age. J Am Heart Assoc 2014; 3:e000340. [PMID: 24721794 PMCID: PMC4187508 DOI: 10.1161/jaha.113.000340] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 01/07/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND Atrial fibrillation (AF), often associated with structural, fibrotic change in cardiac tissues involving regulatory signaling mediators, becomes increasingly common with age. In the present study, we explored the role of mitogen-activated protein kinase kinase 4 (Mkk4), a critical component of the stress-activated mitogen-activated protein kinase family, in age-associated AF. METHODS AND RESULTS We developed a novel mouse model with a selective inactivation of atrial cardiomyocyte Mkk4 (Mkk4(ACKO)). We characterized and compared electrophysiological, histological, and molecular features of young (3- to 4-month), adult (6-month), and old (1-year) Mkk4(ACKO) mice with age-matched control littermates (Mkk4(F/F)). Aging Mkk4(ACKO) mice were more susceptible to atrial tachyarrhythmias than the corresponding Mkk4(F/F) mice, showing characteristic slow and dispersed atrial conduction, for which modeling studies demonstrated potential arrhythmic effects. These differences paralleled increased interstitial fibrosis, upregulated transforming growth factor beta 1 (TGF-β1) signaling and dysregulation of matrix metalloproteinases in Mkk4(ACKO), compared to Mkk4(F/F), atria. Mkk4 inactivation increased the sensitivity of cultured cardiomyocytes to angiotensin II-induced activation of TGF-β1 signaling. This, in turn, enhanced expression of profibrotic molecules in cultured cardiac fibroblasts, suggesting cross-talk between these two cell types in profibrotic signaling. Finally, human atrial tissues in AF showed a Mkk4 downregulation associated with increased production of profibrotic molecules, compared to findings in tissue from control subjects in sinus rhythm. CONCLUSIONS These findings together demonstrate, for the first time, that Mkk4 is a negative regulator of the TGF-β1 signaling associated with atrial remodeling and arrhythmogenesis with age, establishing Mkk4 as a new potential therapeutic target for treating AF.
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Affiliation(s)
- Laura Davies
- Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences, University of Manchester, Manchester, UK (L.D., J.J., H.T., Y.W., Y.Z., G.H., E.J.C., M.L.)
| | - Jiawei Jin
- Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences, University of Manchester, Manchester, UK (L.D., J.J., H.T., Y.W., Y.Z., G.H., E.J.C., M.L.)
- Faculty of Life Science, University of Manchester, Manchester, UK (J.J., X.W.)
| | - Weijin Shen
- School of Physics and Astronomy, University of Manchester, Manchester, UK (W.S., H.Z.)
| | - Hoyee Tsui
- Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences, University of Manchester, Manchester, UK (L.D., J.J., H.T., Y.W., Y.Z., G.H., E.J.C., M.L.)
| | - Ying Shi
- Institute for Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, China (Y.S., J.W., S.C., N.D., M.L.)
| | - Yanwen Wang
- Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences, University of Manchester, Manchester, UK (L.D., J.J., H.T., Y.W., Y.Z., G.H., E.J.C., M.L.)
| | - Yanmin Zhang
- Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences, University of Manchester, Manchester, UK (L.D., J.J., H.T., Y.W., Y.Z., G.H., E.J.C., M.L.)
| | - Guoliang Hao
- Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences, University of Manchester, Manchester, UK (L.D., J.J., H.T., Y.W., Y.Z., G.H., E.J.C., M.L.)
| | - Jingjing Wu
- Institute for Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, China (Y.S., J.W., S.C., N.D., M.L.)
| | - Si Chen
- Institute for Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, China (Y.S., J.W., S.C., N.D., M.L.)
| | - James A. Fraser
- Physiological Laboratory, University of Cambridge, Cambridge, UK (J.A.F., C.L.H.)
| | - Nianguo Dong
- Institute for Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, China (Y.S., J.W., S.C., N.D., M.L.)
| | - Vincent Christoffels
- Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (V.C.)
| | - Ursula Ravens
- Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, Dresden, Germany (U.R.)
| | | | - Henggui Zhang
- School of Physics and Astronomy, University of Manchester, Manchester, UK (W.S., H.Z.)
| | - Elizabeth J. Cartwright
- Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences, University of Manchester, Manchester, UK (L.D., J.J., H.T., Y.W., Y.Z., G.H., E.J.C., M.L.)
| | - Xin Wang
- Faculty of Life Science, University of Manchester, Manchester, UK (J.J., X.W.)
| | - Ming Lei
- Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences, University of Manchester, Manchester, UK (L.D., J.J., H.T., Y.W., Y.Z., G.H., E.J.C., M.L.)
- Institute for Cardiovascular Diseases, Union Hospital, Huazhong University of Science and Technology, Wuhan, China (Y.S., J.W., S.C., N.D., M.L.)
- Department of Pharmacology, University of Oxford, Mansfield Road, UK (M.L.)
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17
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Oxidative stress in atrial fibrillation: an emerging role of NADPH oxidase. J Mol Cell Cardiol 2013; 62:72-9. [PMID: 23643589 DOI: 10.1016/j.yjmcc.2013.04.019] [Citation(s) in RCA: 166] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Revised: 03/22/2013] [Accepted: 04/18/2013] [Indexed: 02/07/2023]
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Patients with AF have up to seven-fold higher risk of suffering from ischemic stroke. Better understanding of etiologies of AF and its thromboembolic complications are required for improved patient care, as current anti-arrhythmic therapies have limited efficacy and off target effects. Accumulating evidence has implicated a potential role of oxidative stress in the pathogenesis of AF. Excessive production of reactive oxygen species (ROS) is likely involved in the structural and electrical remodeling of the heart, contributing to fibrosis and thrombosis. In particular, NADPH oxidase (NOX) has emerged as a potential enzymatic source for ROS production in AF based on growing evidence from clinical and animal studies. Indeed, NOX can be activated by known upstream triggers of AF such as angiotensin II and atrial stretch. In addition, treatments such as statins, antioxidants, ACEI or AT1RB have been shown to prevent post-operative AF; among which ACEI/AT1RB and statins can attenuate NOX activity. On the other hand, detailed molecular mechanisms by which specific NOX isoform(s) are involved in the pathogenesis of AF and the extent to which activation of NOX plays a causal role in AF development remains to be determined. The current review discusses causes and consequences of oxidative stress in AF with a special focus on the emerging role of NOX pathways.
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18
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Ducas R, Ariyarajah V. Atrial Fibrillation in Patients with Ischemic and Non-Ischemic Left Ventricular Dysfunction. J Atr Fibrillation 2013; 5:535. [PMID: 28496804 DOI: 10.4022/jafib.535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2012] [Revised: 09/07/2012] [Accepted: 01/23/2012] [Indexed: 02/01/2023]
Abstract
Atrial fibrillation (AF) and left ventricular dysfunction (LVD) are increasingly common clinical problems, affecting millions of people worldwide. It is well established that the presence of AF portends a poor prognosis in the setting of both ischemic and non-ischemic LVD, and frequently results in worsening clinical status. Many clinical studies and trials have attempted to address treatment options and efficacy; despite this treatment for AF in LVD is still controversial.
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Affiliation(s)
- Robin Ducas
- Section of Cardiology Dept. of Cardiac Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Vignendra Ariyarajah
- Division of Cardiology, The Brooklyn Hospital Center, Weill Cornell Medical College, Brooklyn, New York
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19
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Jensen K, Nizamutdinov D, Guerrier M, Afroze S, Dostal D, Glaser S. General mechanisms of nicotine-induced fibrogenesis. FASEB J 2012; 26:4778-87. [PMID: 22906950 PMCID: PMC3509054 DOI: 10.1096/fj.12-206458] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Accepted: 08/06/2012] [Indexed: 01/06/2023]
Abstract
Cigarette smoking contributes to the development of cancer, and pathogenesis of other diseases. Many chemicals have been identified in cigarettes that have potent biological properties. Nicotine is especially known for its role in addiction and plays a role in other physiological effects of smoking and tobacco use. Recent studies have provided compelling evidence that, in addition to promoting cancer, nicotine also plays a pathogenic role in systems, such as the lung, kidney, heart, and liver. In many organ systems, nicotine modulates fibrosis by altering the functions of fibroblasts. Understanding the processes modulated by nicotine holds therapeutic potential and may guide future clinical and research decisions. This review discusses the role of nicotine in the general fibrogenic process that governs fibrosis and fibrosis-related diseases, focusing on the cellular mechanisms that have implications in multiple organ systems. Potential research directions for the management of nicotine-induced fibrosis, and potential clinical considerations with regard to nicotine-replacement therapy (NRT) are presented.
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Affiliation(s)
| | - Damir Nizamutdinov
- Division of Molecular Cardiology, Department of Internal Medicine, Texas A&M Health Science Center, Central Texas Veterans Health Care System, Temple, Texas, USA; and
| | | | | | - David Dostal
- Division of Molecular Cardiology, Department of Internal Medicine, Texas A&M Health Science Center, Central Texas Veterans Health Care System, Temple, Texas, USA; and
| | - Shannon Glaser
- Division of Gastroenterology and
- Scott and White Healthcare Digestive Disease Research Center, Temple, Texas, USA
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20
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Qin M, Huang H, Wang T, Hu H, Liu Y, Gu Y, Cao H, Li H, Huang C. Atrial tachyarrhythmia in Rgs5-null mice. PLoS One 2012; 7:e46856. [PMID: 23144791 PMCID: PMC3489853 DOI: 10.1371/journal.pone.0046856] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Accepted: 09/07/2012] [Indexed: 12/19/2022] Open
Abstract
AIMS The aim of this study was to elucidate the effects of regulator of G-protein signaling 5 (Rgs5), a negative regulator of G protein-mediated signaling, on atrial repolarization and tachyarrhythmia (ATA) in mice. METHODS AND RESULTS In present study, the incidence of ATA were increased in Rgs5(-/-) Langendorff-perfused mouse hearts during program electrical stimulation (PES) (46.7%, 7 of 15) and burst pacing (26.7%, 4 of 15) compared with wild-type (WT) mice (PES: 7.1%,1 of 14; burst:7.1%,1 of 14) (P<0.05). And the duration of ATA also shown longer in Rgs5(-/-) heart than that in WT, 2 out of 15 hearts exhibited sustained ATA (>30 s) but none of them observed in WT mice. Atrial prolonged repolarization was observed in Rgs5(-/-) hearts including widened P wave in surface ECG recording, increased action potential duration (APD) and atrial effective refractory periods (AERP), all of them showed significant difference with WT mice (P<0.05). At the cellular level, whole-cell patch clamp recorded markedly decreased densities of repolarizing K(+) currents including I(Kur) (at +60 mV: 14.0±2.2 pF/pA) and I(to) (at +60 mV: 16.7±1.3 pA/pF) in Rgs5(-/-) atrial cardiomyocytes, compared to those of WT mice (at +60 mV I(to): 20.4±2.0 pA/pF; I(kur): 17.9±2.0 pF/pA) (P<0.05). CONCLUSION These results suggest that Rgs5 is an important regulator of arrhythmogenesis in the mouse atrium and that the enhanced susceptibility to atrial tachyarrhythmias in Rgs5(-/-) mice may contribute to abnormalities of atrial repolarization.
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Affiliation(s)
- Mu Qin
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - He Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - Teng Wang
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - He Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - Yu Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yongwei Gu
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - Hong Cao
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - Hongliang Li
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
| | - Congxin Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- * E-mail:
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Wen H, Gwathmey JK, Xie LH. Oxidative stress-mediated effects of angiotensin II in the cardiovascular system. World J Hypertens 2012; 2:34-44. [PMID: 24587981 PMCID: PMC3936474 DOI: 10.5494/wjh.v2.i4.34] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Angiotensin II (Ang II), an endogenous peptide hormone, plays critical roles in the pathophysiological modulation of cardiovascular functions. Ang II is the principle effector of the renin-angiotensin system for maintaining homeostasis in the cardiovascular system, as well as a potent stimulator of NAD(P)H oxidase, which is the major source and primary trigger for reactive oxygen species (ROS) generation in various tissues. Recent accumulating evidence has demonstrated the importance of oxidative stress in Ang II-induced heart diseases. Here, we review the recent progress in the study on oxidative stress-mediated effects of Ang II in the cardiovascular system. In particular, the involvement of Ang II-induced ROS generation in arrhythmias, cell death/heart failure, ischemia/reperfusion injury, cardiac hypertrophy and hypertension are discussed. Ca2+/calmodulin-dependent protein kinase II is an important molecule linking Ang II, ROS and cardiovascular pathological conditions.
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Chang C, Zhang C, Zhao X, Kuang X, Tang H, Xiao X. Differential regulation of mitogen-activated protein kinase signaling pathways in human with different types of mitral valvular disease. J Surg Res 2012; 181:49-59. [PMID: 22664133 DOI: 10.1016/j.jss.2012.05.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Revised: 04/11/2012] [Accepted: 05/08/2012] [Indexed: 02/05/2023]
Abstract
BACKGROUND Mitogen-activated protein kinases (MAPKs) are considered to play a prominent role in cardiac development, function, and pathogenesis. The different types of mitral valvular disease (MVD), including mitral regurgitation (MR) and mitral stenosis (MS), have different underlying pathophysiologic changes, but the precise intracellular signal transduction mechanisms are not clear. Thus, we investigated the differential regulation of MAPK signaling pathways in humans with different types of MVD. METHODS Left atrial appendage tissue samples from 32 patients with MVD who were undergoing mitral valve replacement surgery were studied. Serum angiotensin II concentrations were measured using enzyme-linked immunosorbent assay. The expression of MAPK pathway-related genes and proteins was assessed using quantitative polymerase chain reaction, Western blot, and immunohistochemistry. RESULTS Echocardiography showed that patients with MS had a greater left atrial pressure overload than those with MR. The relative amounts of angiotensin II, extracellular signal-regulated kinase 1, p38α, c-Jun N-terminal kinase 2, c-Fos, activating transcription factor 2, and c-Jun mRNA were significantly upregulated in those with MS compared with those with MR (P < 0.05). The serum angiotensin II concentrations were significantly increased in those with MS compared with those with MR (P = 0.017). Substantial changes in the phosphorylated forms of the MAPK proteins were detected. Phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated p38 were significantly increased in those with MS compared with those with MR (P < 0.001), and phosphorylated c-Jun N-terminal kinase in the MR group was significantly greater than that in the MS group (P < 0.001). Histologically, more serious myocardial cells losses, myolysis, and interstitial fibrosis were detected in the MS group. CONCLUSIONS The different types of MVD have different hemodynamic characteristics, and different MAPK pathways were activated in the MR and MS groups, which could lead to diverse left atrial histologic changes.
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Affiliation(s)
- Chao Chang
- Department of Thoracic and Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
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Atrial fibrillation and heart failure parallels: lessons for atrial fibrillation prevention. Crit Pathw Cardiol 2011; 10:46-51. [PMID: 21562376 DOI: 10.1097/hpc.0b013e31820e1a4b] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Heart failure (HF) and atrial fibrillation (AF) are 2 of the most common cardiovascular diseases encountered in clinical practice, and the prevalence of these diseases continues to grow worldwide with the aging of the global population. While recognizing that AF is a heterogeneous disorder, we submit that the parallels between AF and HF may arise because many cases of AF and HF result from the cumulative exposure of the atria and ventricles to a common set of systemic cardiovascular risk factors. Over time, exposure to risk factors promotes development of atrial and ventricular structural and functional abnormalities through activation of several biologic pathways in concert: upregulation of neurohormonal signaling cascades, release of inflammatory mediators, programmed cell death, and fibrosis. Cardiac structural remodeling occurs in concert with electrophysiologic remodeling, both of which contribute to atrial and ventricular rhythm disturbances, including AF. AF and HF, instead of representing distinct disease processes, often represent different endpoints along a disease continuum. By reviewing some of the mechanistic parallels between AF and HF, we hope to emphasize the connection between established cardiovascular risk factors, cardiac remodeling and AF, with a view to promote strategies for AF prevention.
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Shathasivam T, Kislinger T, Gramolini AO. Genes, proteins and complexes: the multifaceted nature of FHL family proteins in diverse tissues. J Cell Mol Med 2011; 14:2702-20. [PMID: 20874719 PMCID: PMC3822721 DOI: 10.1111/j.1582-4934.2010.01176.x] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Four and a half LIM domain protein 1 (FHL1) is the founding member of the FHL family of proteins characterized by the presence of four and a half highly conserved LIM domains. The LIM domain is a protein-interaction motif and is involved in linking proteins with both the actin cytoskeleton and transcriptional machinery. To date, more than 25 different protein interactions have been identified for full length FHL1 and its spliced variants, and these interactions can be mapped to a variety of functional classes. Because FHL1 is expressed predominantly in skeletal muscle, all of these proteins interactions translate into a multifunctional and integral role for FHL1 in muscle development, structural maintenance, and signalling. Importantly, 27 FHL1 genetic mutations have been identified that result in at least six different X-linked myopathies, with patients often presenting with cardiovascular disease. FHL1 expression is also significantly up-regulated in a variety of cardiac disorders, even at the earliest stages of disease onset. Alternatively, FHL1 expression is suppressed in a variety of cancers, and ectopic FHL1 expression offers potential for some phenotype rescue. This review focuses on recent studies of FHL1 in muscular dystrophies and cardiovascular disease, and provides a comprehensive review of FHL1s multifunctional roles in skeletal muscle.
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Xiao J, Liang D, Zhang Y, Liu Y, Zhang H, Liu Y, Li L, Liang X, Sun Y, Chen YH. MicroRNA expression signature in atrial fibrillation with mitral stenosis. Physiol Genomics 2011; 43:655-64. [PMID: 21325063 DOI: 10.1152/physiolgenomics.00139.2010] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The aim of this study was to investigate the microRNA (miRNA) signature in atrial fibrillation (AF) with mitral stenosis (MS). miRNA arrays were used to evaluate the expression signature of the right atrial appendages of healthy individuals (n=9), patients with MS and AF (n=9) and patients with MS without AF (n=4). The results were validated with qRT-PCR analysis. GOmir was used to predict the potential miRNA targets and to analyze their functions. DIANA-mirPath was used to incorporate the miRNAs into pathways. miRNA arrays revealed that 136 and 96 miRNAs were expressed at different levels in MS patients with AF and in MS patients without AF, respectively, compared with healthy controls. More importantly, 28 miRNAs were expressed differently in the MS patients with AF compared with the MS patients without AF; of these miRNAs, miR-1202 was the most dysregulated. The unsupervised hierarchical clustering analysis based on the 28 differently expressed miRNAs showed that the heat map of miRNA expression categorized two well-defined clusters that corresponded to MS with AF and MS without AF. The qRT-PCR results correlated well with the microarray data. Bioinformatic analysis indicated the potential miRNA targets and molecular pathways. This study shows that there is a distinct miRNA expression signature in AF with MS. The findings may be useful for the development of therapeutic interventions that are based on rational target selection in these patients.
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Affiliation(s)
- Junjie Xiao
- Key Laboratory of Arrhythmias, Ministry of Education, Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, China
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Castillo R, Rodrigo R, Perez F, Cereceda M, Asenjo R, Zamorano J, Navarrete R, Villalabeitia E, Sanz J, Baeza C, Aguayo R. Antioxidant therapy reduces oxidative and inflammatory tissue damage in patients subjected to cardiac surgery with extracorporeal circulation. Basic Clin Pharmacol Toxicol 2010; 108:256-62. [PMID: 21138533 DOI: 10.1111/j.1742-7843.2010.00651.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Ischaemia reperfusion injury is a pathophysiological event that occurs after cardiac surgery with extracorporeal circulation. This clinical event has been associated with the induction of oxidative and inflammatory damage in atrial tissue. Here, we tested whether combined omega 3 polyunsaturated fatty acids (n-3 PUFA)-antioxidant vitamin protocol therapy reduces oxidative and inflammatory cardiac tissue damage. This trial assigned 95 either-sex patients to supplementation with n-3 PUFA (2 g/day), or matching placebo groups, 7 days before on-pump surgery. Antioxidant vitamins C (1 g/day) and E (400 IU/day) or placebo were added from 2 days before surgery until discharge. Blood and atrial tissue samples were obtained during the intervention. Reduced/oxidized glutathione (GSH/GSSG) ratio, malondialdehyde (MDA) and protein carbonylation were determined in atrial tissue. Leucocyte count and high-sensitivity C-reactive protein (hs-CRP) in blood plus nuclear factor (NF)-κappaB activation in atrial tissue served for inflammation assessment. Lipid peroxidation and protein carbonylation were 27.5 and 24% lower in supplemented patients (p < 0.01). GSH/GSSG ratio was 38.1% higher in supplemented patients compared with placebo (p < 0.01). Leucocyte count and serum hs-CRP levels were markedly lower throughout the protocol in supplemented patients (p < 0.01). Atrial tissue NF-κB DNA activation in supplemented patients was 22.5% lower than that in placebo patients (p < 0.05). The combined n-3 PUFA-antioxidant vitamin protocol therapy here proposed reduced the oxidative stress and inflammation biomarkers, in patients undergoing on-pump cardiac surgery.
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Affiliation(s)
- Rodrigo Castillo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
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Liu E, Yang S, Xu Z, Li J, Yang W, Li G. Angiotensin-(1-7) prevents atrial fibrosis and atrial fibrillation in long-term atrial tachycardia dogs. ACTA ACUST UNITED AC 2010; 162:73-8. [PMID: 20074590 DOI: 10.1016/j.regpep.2009.12.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2009] [Revised: 12/16/2009] [Accepted: 12/30/2009] [Indexed: 10/20/2022]
Abstract
Renin-angiotensin system (RAS) is activated in the fibrillating atria. Angiotensin-(1-7) [Ang-(1-7)] counterbalances the actions of angiotensin II (Ang II). To investigate the effects of Ang-(1-7) on the long-term atrial tachycardia-induced atrial fibrosis and atrial fibrillation (AF) vulnerability, eighteen dogs were assigned to sham group, paced group, or paced+Ang-(1-7) group, 6 dogs in each group. Rapid atrial pacing at 500 bpm was maintained for 14 days, but dogs in the sham group were instrumented without pacing. During the pacing, Ang-(1-7) (6 microg x kg(-1) x h(-1)) was given intravenously. After pacing, atrial mRNA expression of ERK1/ERK2 and atrial fibrosis were assessed, the inducibility and duration of AF were measured. Compared with sham, ERK1/ERK2 mRNA expression was increased in the paced group (P<0.05). Atrial tissue from the paced dogs showed a large amount of interstitial fibrosis, and the inducible rate of AF was increased at various BCLs in paced dogs (P<0.01). Compared with the paced group, Ang-(1-7) prevented the increase of ERK1/ERK2 mRNA expression (P<0.01 and P<0.05, respectively), and attenuated the interstitial fibrosis (P<0.01). Inducibility and duration of AF were reduced by Ang-(1-7) at various BCLs. In conclusion, Ang-(1-7) reduced AF vulnerability in chronic paced atria, and antifibrotic actions contributed to its preventive effects on AF.
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Affiliation(s)
- Enzhao Liu
- Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
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Primary and secondary prevention of atrial fibrillation with statins and polyunsaturated fatty acids: review of evidence and clinical relevance. Naunyn Schmiedebergs Arch Pharmacol 2009; 381:1-13. [PMID: 19937318 DOI: 10.1007/s00210-009-0468-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2009] [Accepted: 10/15/2009] [Indexed: 01/29/2023]
Abstract
Atrial fibrillation (AF) is an increasingly common arrhythmia that now stands at epidemic proportion, with more than 2.3 million people affected in the USA and over 4.5 million people affected in Western Europe. AF is an expression of underlying heart disease and is increasingly associated with hypertension, congestive heart failure, and ischemic heart disease. It is also a progressive disease secondary to continuous structural remodeling of the atria, which relates to AF itself, to changes associated with aging and to progression of the underlying heart disease. Traditionally, AF has been addressed only after it has already presented with pharmacological and nonpharmacological therapies designed for rhythm or rate control (secondary prevention). Although secondary prevention is the most feasible approach at present, the concept of primary prevention of AF with therapies aimed at preventing the development of substrate and correcting the risk factors for AF has emerged as a strategy, which is likely to produce a larger effect in the general population. Recent experiments provided new insights into AF pathophysiology, which generated background for new mechanism-based therapies. Agents targeting inflammation, oxidative injury, atrial myocyte metabolism, extracellular matrix remodeling, and fibrosis have theoretical advantages as novel therapeutic strategies. In this respect, drugs that are not traditionally antiarrhythmic such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, aldosterone antagonists, statins, and omega-3 polyunsaturated fatty acids have shown an antiarrhythmic potential in addition to any treatment effect on the underlying disease. These agents are thought to have an advantage of targeting both the occurrence and progression of the substrate for AF, thus, providing primary and secondary prevention of the arrhythmia. Although first experimental and hypothesis-generating small clinical studies or retrospective analyses have been encouraging, several larger, properly designed, prospective trials have not confirmed earlier observations. This review provides a contemporary evidence-based insight into the possible preventative and reverse remodeling role of statins and polyunsaturated fatty acids in AF.
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The predictive value of inflammatory and oxidative markers following the successful cardioversion of persistent lone atrial fibrillation. Int J Cardiol 2009; 135:361-9. [DOI: 10.1016/j.ijcard.2008.04.012] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2007] [Revised: 02/06/2008] [Accepted: 04/04/2008] [Indexed: 11/15/2022]
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Goette A. Nicotine, atrial fibrosis, and atrial fibrillation: do microRNAs help to clear the smoke? Cardiovasc Res 2009; 83:421-2. [PMID: 19502283 DOI: 10.1093/cvr/cvp188] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Gramley F, Lorenzen J, Koellensperger E, Kettering K, Weiss C, Munzel T. Atrial fibrosis and atrial fibrillation: the role of the TGF-β1 signaling pathway. Int J Cardiol 2009; 143:405-13. [PMID: 19394095 DOI: 10.1016/j.ijcard.2009.03.110] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2008] [Revised: 02/23/2009] [Accepted: 03/24/2009] [Indexed: 10/20/2022]
Abstract
BACKGROUND Atrial fibrosis concurs with chronic atrial fibrillation (AF), a phenomenon that contributes to the resistance to restore and maintain sinus rhythm (SR). Fibrogenesis represents a complex process in which the transforming growth factor-β1 (TGF-β1) pathway may play a major role, e.g. in the setting of myocardial infarction. The present study addresses the potential contribution of the TGF-β1 signaling pathway to atrial fibrosis in patients with AF. METHODS AND RESULTS Right atrial appendages of 163 patients were excised during heart surgery and grouped according to rhythm (SR vs. AF) and AF duration. Five groups were defined: SR, paroxysmal/chronic persistent AF (<6 months), chronic permanent AF (CAF) of 7-24 months, 25-60 months, and >60 months duration. Collagen content of atria, determined morphometrically, revealed a steady and significant increase in patients with SR (14.6±8.9%) up to patients with CAF of >60 months (28.1±7.1%). Likewise, expression of TGF-β1 mRNA and protein, TGF-β-receptor-II protein, profibrotic phospho-Smad-2 and -4 proteins increased. However, the TGF-β(1) effect appeared to decline with increasing AF duration, characterized by a decrease in TGF-β-receptor-I protein, increases of TGF-β inhibiting Smad-7 protein and a reduction of ph-Smad-2. CONCLUSIONS Human atrial fibrogenesis in patients with atrial fibrillation is accompanied by a biphasic response, an early increase and later loss of responsiveness to TGF-β(1). It appears that fibrosis progresses despite compensatory changes in the TGF-β-signaling pathway. The sequential changes in the contribution of different profibrotic processes during the establishment of AF may offer the opportunity to selectively interfere with the atrial remodeling process at different stages.
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Affiliation(s)
- Felix Gramley
- Department of Cardiology and Vascular Medicine, Mainz University, Germany.
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Hirose M, Takeishi Y, Niizeki T, Shimojo H, Nakada T, Kubota I, Nakayama J, Mende U, Yamada M. Diacylglycerol kinase ζ inhibits Gαq-induced atrial remodeling in transgenic mice. Heart Rhythm 2009; 6:78-84. [DOI: 10.1016/j.hrthm.2008.10.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2008] [Accepted: 10/10/2008] [Indexed: 10/21/2022]
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Le Heuzey JY, Marijon E, Chachoua K, Waintraub X, Lepillier A, Otmani A, Lavergne T, Pornin M. Pathophysiology of atrial fibrillation: insights into the renin-angiotensin system. Arch Cardiovasc Dis 2008; 101:787-91. [PMID: 19059574 DOI: 10.1016/j.acvd.2008.09.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2008] [Revised: 09/19/2008] [Accepted: 09/21/2008] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Atrial fibrillation is, to date, a major problem of public health with an important cost in the health care system. DISCUSSION The therapeutic strategies for atrial fibrillation are complex and their outcomes have been disappointing globally. New ablative techniques have brought important advances but the patient's profile has to be taken into account in the choice of the therapeutic strategies. The renin-angiotensin system plays a major role in the phenomena of remodelling following the onset of atrial fibrillation. CONCLUSION Drugs blocking the renin-angiotensin system can have a real place in the treatment of atrial fibrillation, not only to maintain sinus rhythm but primarily to prevent cardiovascular accidents in these patients with atrial fibrillation and in some cases to prevent the occurrence of atrial fibrillation, for example in hypertensive patients.
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Affiliation(s)
- Jean-Yves Le Heuzey
- Service de cardiologie A et rythmologie, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France.
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Abstract
Abnormal excitability of myocardial cells may give rise to ectopic beats and initiate re-entry around an anatomical or functional obstacle. As K(+) currents control the repolarization process of the cardiac action potential (AP), the K(+) channel function determines membrane potential and refractoriness of the myocardium. Both gain and loss of the K(+) channel function can lead to arrhythmia. The former because abbreviation of the active potential duration (APD) shortens refractoriness and wave length, and thereby facilitates re-entry and the latter because excessive prolongation of APD may lead to torsades de pointes (TdP) arrhythmia and sudden cardiac death. The pro-arrhythmic consequences of malfunctioning K(+) channels in ventricular and atrial tissue are discussed in the light of three pathophysiologically relevant aspects: genetic background, drug action, and disease-induced remodelling. In the ventricles, loss-of-function mutations in the genes encoding for K(+) channels and many drugs (mainly hERG channel blockers) are related to hereditary and acquired long-QT syndrome, respectively, that put individuals at high risk for developing TdP arrhythmias and life-threatening ventricular fibrillation. Similarly, down-regulation of K(+) channels in heart failure also increases the risk for sudden cardiac death. Mutations and polymorphisms in genes encoding for atrial K(+) channels can be associated with gain-of-function and shortened, or with loss-of-function and prolonged APs. The block of atrial K(+) channels becomes a particular therapeutic challenge when trying to ameliorate atrial fibrillation (AF). This arrhythmia has a strong tendency to cause electrical remodelling, which affects many K(+) channels. Atrial-selective drugs for the treatment of AF without affecting the ventricles could target structures such as I(Kur) or constitutively active I(K,ACh) channels.
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Affiliation(s)
- Ursula Ravens
- Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, Dresden, Germany.
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Abstract
Atrial fibrillation (AF) is an epidemic, affecting 1% to 1.5% of the population in the developed world. Projected data from the population-based studies suggest that the prevalence of AF will grow at least 3-fold by 2050. The health and economic burden imposed by AF and AF-related morbidity is enormous. Atrial fibrillation has a multiplicity of causes ranging from genetic to degenerative, but hypertension and heart failure are the commonest and epidemiologically most prevalent conditions associated with AF as both have been shown to create an arrhythmogenic substrate. Several theories emerged regarding the mechanism of AF, which can be combined into two groups: the single focus hypothesis and the multiple sources hypothesis. Several lines of evidence point to the relevance of both hypotheses to the mechanism of AF, probably with a different degree of involvement depending on the variety of AF (paroxysmal or persistent). Sustained AF alters electrophysiological and structural properties of the atrial myocardium such that the atria become more susceptible to the initiation and maintenance of the arrhythmia, a process known as atrial remodeling. Angiotensin II has been recognized as a key element in atrial remodeling in association with AF opening the possibility of exploitation of "upstream" therapies to prevent or delay atrial remodeling. The clinical significance of AF lies predominantly in a 5-fold increased risk of stroke. The limitations of warfarin prompted the development of new antithrombotic drugs, which include anticoagulants, such as direct oral thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban). Novel mechanical approaches for the prevention of cardioembolic stroke have recently been evaluated: percutaneous left atrial appendage occluders, minimally invasive surgical isolation of the left atrial appendage, and implantation of carotid filtering devices.
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Affiliation(s)
- Irina Savelieva
- St George's University of London, Cranmer Terrace, London, U.K
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Rodrigo R, Cereceda M, Castillo R, Asenjo R, Zamorano J, Araya J, Castillo-Koch R, Espinoza J, Larraín E. Prevention of atrial fibrillation following cardiac surgery: basis for a novel therapeutic strategy based on non-hypoxic myocardial preconditioning. Pharmacol Ther 2008; 118:104-27. [PMID: 18346791 DOI: 10.1016/j.pharmthera.2008.01.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2008] [Accepted: 01/24/2008] [Indexed: 02/06/2023]
Abstract
Atrial fibrillation is the most common complication of cardiac surgical procedures performed with cardiopulmonary bypass. It contributes to increased hospital length of stay and treatment costs. At present, preventive strategies offer only suboptimal benefits, despite improvements in anesthesia, surgical technique, and medical therapy. The pathogenesis of postoperative atrial fibrillation is considered to be multifactorial. However oxidative stress is a major contributory factor representing the unavoidable consequences of ischemia/reperfusion cycle occurring in this setting. Considerable evidence suggests the involvement of reactive oxygen species (ROS) in the pathogenic mechanism of this arrhythmia. Interestingly, the deleterious consequences of high ROS exposure, such as inflammation, cell death (apoptosis/necrosis) or fibrosis, may be abrogated by a myocardial preconditioning process caused by previous exposure to moderate ROS concentration known to trigger survival response mechanisms. The latter condition may be created by n-3 PUFA supplementation that could give rise to an adaptive response characterized by increased expression of myocardial antioxidant enzymes and/or anti-apoptotic pathways. In addition, a further reinforcement of myocardial antioxidant defenses could be obtained through vitamins C and E supplementation, an intervention also known to diminish enzymatic ROS production. Based on this paradigm, this review presents clinical and experimental evidence supporting the pathophysiological and molecular basis for a novel therapeutic approach aimed to diminish the incidence of postoperative atrial fibrillation through a non-hypoxic preconditioning plus a reinforcement of the antioxidant defense system in the myocardial tissue.
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Affiliation(s)
- Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
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Lin CS, Lai LP, Lin JL, Sun YL, Hsu CW, Chen CL, Mao SJT, Huang SKS. Increased expression of extracellular matrix proteins in rapid atrial pacing-induced atrial fibrillation. Heart Rhythm 2007; 4:938-49. [PMID: 17599682 DOI: 10.1016/j.hrthm.2007.03.034] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2007] [Accepted: 03/21/2007] [Indexed: 10/23/2022]
Abstract
BACKGROUND Atrial fibrillation (AF) is characterized by structural remodeling of the extracellular matrix (ECM) in cardiac atrium. OBJECTIVE The purpose of this study was to gain further insight into atrial ECM remodeling at the molecular level and to test whether altered expression of ECM proteins was associated with the disease. METHODS Sustained AF was induced in nine adult pigs after 3-4 weeks of continuous rapid atrial pacing at a rate of 600 bpm. Histologic studies and immunohistochemical stain were performed to identify the potential pathologic substrate underlying abnormalities in atrial tissues with sustained AF. RESULTS In the pathologic findings, the fraction of myocardial ECM (ECM%) was measured, with a significantly greater ECM% found in the AF group compared with the sham operated group (n = 6; i.e., pigs with normal sinus rhythm [SR]). A set of 9,182 genes was screened with cDNA microarray analysis. In AF animals, expression of 121 genes increased and 24 genes decreased by > or =1.75-fold compared with SR animals. Significant up-regulation of fibronectin-1 (4.9-fold), fibrillin-1 (3.1-fold), and fibromodulin (1.9-fold) in the fibrillating atria was confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction. Western blot analysis revealed significantly increased atrial fibronectin-1, fibrillin-1, and fibromodulin in the AF group compared with the SR group (1.5-, 2.7-, and 2.1-fold, respectively). Immunohistochemical staining of AF tissue displayed increased accumulation of fibronectin-1 and fibrillin-1 in the atrial interstitial space. CONCLUSION Increased expression of ECM proteins in fibrillating atria supports the hypothesis that ECM metabolism contributes to the development of AF.
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Affiliation(s)
- Chih-Sheng Lin
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
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Chen CL, Lin JL, Lai LP, Pan CH, Huang SKS, Lin CS. Altered expression of FHL1, CARP, TSC-22 and P311 provide insights into complex transcriptional regulation in pacing-induced atrial fibrillation. Biochim Biophys Acta Mol Basis Dis 2007; 1772:317-29. [PMID: 17174532 DOI: 10.1016/j.bbadis.2006.10.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2006] [Revised: 10/23/2006] [Accepted: 10/24/2006] [Indexed: 11/28/2022]
Abstract
Atrial fibrillation (AF) is the most common progressive disease in patients with cardiac arrhythmia. AF is accompanied by complex atrial remodeling and changes in gene expression, but only a limited number of transcriptional regulators have been identified. Using a low-density cDNA array, we identified 31 genes involved in transcriptional regulation, signal transduction or structural components, which were either significantly upregulated or downregulated in porcine atria with fibrillation (induced by rapid atrial pacing at a rate of 400-600 bpm for 4 weeks that was then maintained without pacing for 2 weeks). The genes for four and a half LIM domains protein-1 (FHL1), transforming growth factor-beta (TGF-beta)-stimulated clone 22 (TSC-22), and cardiac ankyrin repeat protein (CARP) were significantly upregulated, and chromosome 5 open reading frame gene 13 (P311) was downregulated in the fibrillating atria. FHL1 and CARP play important regulatory roles in cardiac remodeling by transcriptional regulation and myofilament assembly. Induced mRNA expression of both FHL1 and CARP was also observed when cardiac H9c2 cells were treated with an adrenergic agonist. Increasing TSC-22 and marked P311 deficiency could enhance the activity of TGF-beta signaling and the upregulated TGF-beta1 and -beta2 expressions were identified in the fibrillating atria. These results implicate that observed alterations of underlying molecular events were involved in the rapid-pacing induced AF, possibly via activation of the beta-adrenergic and TGF-beta signaling.
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Affiliation(s)
- Chien-Lung Chen
- Department of Biological Science and Technology, National Chiao Tung University, 75 Po-Ai Street, Hsinchu 30005, Taiwan
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Avila G, Medina IM, Jiménez E, Elizondo G, Aguilar CI. Transforming growth factor-β1 decreases cardiac muscle L-type Ca2+ current and charge movement by acting on the Cav1.2 mRNA. Am J Physiol Heart Circ Physiol 2007; 292:H622-31. [PMID: 16980347 DOI: 10.1152/ajpheart.00781.2006] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Transforming growth factors-β (TGF-βs) are essential to the structural remodeling seen in cardiac disease and development; however, little is known about potential electrophysiological effects. We hypothesized that chronic exposure (6–48 h) of primary cultured neonatal rat cardiomyocytes to the type 1 TGF-β (TGF-β1, 5 ng/ml) may affect voltage-dependent Ca2+ channels. Thus we investigated T- ( ICaT) and L-type ( ICaL) Ca2+ currents, as well as dihydropyridine-sensitive charge movement using the whole cell patch-clamp technique and quantified CaV1.2 mRNA levels by real-time PCR assay. In ventricular myocytes, TGF-β1 did not exert significant electrophysiological effects. However, in atrial myocytes, TGF-β1 reduced both ICaL and charge movement (55% at 24–48 h) without significantly altering ICaT, cell membrane capacitance, or channel kinetics (voltage dependence of activation and inactivation, as well as the activation and inactivation rates). Reductions of ICaL and charge movement were explained by concomitant effects on the maximal values of L-channels conductance ( Gmax) and charge movement (Qmax). Thus TGF-β1 selectively reduces the number of functional L-channels on the surface of the plasma membrane in atrial but not ventricular myocytes. The TGF-β1-induced ICaL reduction was unaffected by supplementing intracellular recording solutions with okadaic acid (2 μM) or cAMP (100 μM), two compounds that promote L-channel phosphorylation. This suggests that the decreased number of functional L-channels cannot be explained by a possible regulation in the L-channels phosphorylation state. Instead, we found that TGF-β1 decreases the expression levels of atrial CaV1.2 mRNA (70%). Thus TGF-β1 downregulates atrial L-channel expression and may be therefore contributing to the in vivo cardiac electrical remodeling.
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Affiliation(s)
- Guillermo Avila
- G. Avila, Dept. of Biochemistry, Cinvestav, Mexico DF 007000, Mexico.
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Huang Y, Lu MQ, Li H, Xu C, Yi SH, Chen GH. Occurrence of cGMP/nitric oxide-sensitive store-operated calcium entry in fibroblasts and its effect on matrix metalloproteinase secretion. World J Gastroenterol 2006; 12:5483-9. [PMID: 17006985 PMCID: PMC4088230 DOI: 10.3748/wjg.v12.i34.5483] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the existence of Nitric oxide/cGMP sensitive store-operated Ca2+ entry in mouse fibroblast NIH/3T3 cells and its influence on matrix metalloproteinase (MMP) production and adhesion ability of fibroblasts.
METHODS: NIH/3T3 cells were cultured. Confocal laser scanning microscopy was used to examine the existence of thapsigargin-induced store-operated Ca2+ entry in fibroblasts. Gelatin zymography and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) were employed to detect the involvement of [Ca2+]i and NO/cGMP in MMP secretion. The involvement of NO/cGMP-sensitive Ca2+ entry in adhesion was determined using matrigel-coated culture plates.
RESULTS: 8-bromo-cGMP inhibited the thapsigargin-induced Ca2+ entry in 3T3 cells. The cGMP-induced inhibition was abolished by an inhibitor of protein kinase G, KT5823 (1μmol/L). A similar effect on the Ca2+ entry was observed in 3T3 cells in response to a NO donor, (±)-S-nitroso-N-acetylpenicillamine (SNAP). The inhibitory effect of SNAP on the thapsigargin-induced Ca2+ entry was also observed, indicating NO/cGMP-regulated Ca2+ entry in 3T3 cells. Results of gelatin zymography assay showed that addition of extracellular Ca2+ concentration induced MMP release and activation in a dose-dependent manner. RT-PCR also showed that cGMP and SNAP reduced the production of MMP mRNA in 3T3 cells. Experiments investigating adhesion potentials demonstrated that cGMP and SNAP could upgrade 3T3 cell attachment rate to the matrigel-coated culture plates.
CONCLUSION: NO/cGMP sensitive store-operated Ca2+ entry occurs in fibroblasts, and attenuates their adhesion potentials through its influence on MMP secretion.
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Affiliation(s)
- Yong Huang
- Liver Transplantation Centre, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
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Choudhury A, Varughese GI, Lip GYH. Targeting the renin-angiotensin-aldosterone-system in atrial fibrillation: a shift from electrical to structural therapy? Expert Opin Pharmacother 2005; 6:2193-207. [PMID: 16218881 DOI: 10.1517/14656566.6.13.2193] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Despite its increasing incidence and prevalence, treatment options in atrial fibrillation (AF) are far from ideal and often limited. After decades of focus on the electrical aspects of AF with unsatisfactory results, recent research is focusing increasingly on the atrial structural remodelling that underlies the development of AF in different pathological conditions, such as hypertension, heart failure, diabetes mellitus and coronary artery disease. The aim of this review is to provide a comprehensive overview of the role of the renin-angiotensin-aldosterone-system in AF and to highlight the clinical evidence on renin-angiotensin-aldosterone-system blockade as a therapeutic option in AF.
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Affiliation(s)
- Anirban Choudhury
- University Department of Medicine, City Hospital, Birmingham B18 7QH, UK
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Lozano HF, Conde CA, Florin T, Lamas GA. Treatment and prevention of atrial fibrillation with nonantiarrhythmic pharmacologic therapy. Heart Rhythm 2005; 2:1000-7. [PMID: 16171759 DOI: 10.1016/j.hrthm.2005.05.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2005] [Accepted: 05/24/2005] [Indexed: 11/28/2022]
Abstract
Atrial fibrillation is one of the most frequent heart rhythm disturbances found in clinical practice. Anticoagulation, rate control, cardioversion, and ablative procedures have been the mainstay of treatment. The frequent recurrence of atrial fibrillation and the side effects when antiarrhythmic drugs are used have led to dissatisfaction with available treatment of this arrhythmia. Pharmacologic therapy with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, and perhaps aldosterone and calcium channel blockers may have a role in the prevention of atrial fibrillation onset and recurrence. We summarize the possible biologic mechanisms and the clinical observations supporting the use of non-antiarrhythmic medications in the prevention of atrial fibrillation.
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Affiliation(s)
- Hector F Lozano
- Division of Cardiology, Mount Sinai Medical Center, Miami Beach, Florida 33140, USA
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Huang Y, Jiang J, Dou K, Chen Z. HAb18G/CD147 enhances the secretion of matrix metalloproteinases (MMP) via cGMP/NO-sensitive capacitative calcium entry (CCE) and accordingly attenuates adhesion ability of fibroblasts. Eur J Cell Biol 2005; 84:59-73. [PMID: 15724816 DOI: 10.1016/j.ejcb.2004.09.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
The present study examined the effect of hepatoma-associated antigen HAb18G (homologous to CD147) expression on the NO/cGMP-regulated Ca2+ mobilization to induce matrix metalloproteinases (MMP) production and attenuate adhesion ability of mouse fibroblast NIH/3T3 cells. HAb18G/CD147 cDNA was transfected into fibroblast 3T3 cells to obtain a cell line stably expressing HAb18G/CD147, t3T3, as demonstrated by immunofluorescence staining and flow cytometry assays. 8-Bromo-cGMP inhibited the thapsigargin-induced Ca2+ entry in 3T3 cells, whereas an inhibitor of protein kinase G, KT5823 (1 microM), led to an increase in Ca2+ entry. Expression of HAb18G/CD147 in t3T3 cells decreased the inhibitory response to cGMP. A similar effect on the Ca2+ entry was observed in 3T3 cells in response to an NO donor, (+/-)-S-nitroso-N-acetylpenicillamine (SNAP). The inhibitory effect of SNAP on the thapsigargin-induced Ca2+ entry was also reduced in HAb18G/CD147-expressing t3T3 cells, indicating a role for HAb18G/CD 147 in NO/cGMP-regulated Ca2+ entry. Results of gelatin zymography assays showed that addition of extracellular Ca2+ induced MMP (MMP-2, MMP-9) release and activation in a dose-dependent manner, and expression of HAb18G/CD147 enhanced the secretion of MMP-2 and MMP-9 in 3T3 cells. 8-Bromo-cGMP and SNAP reduced the production of MMP in 3T3 cells but not in t3T3 with HAb18G/CD147 expression. RT-PCR experiments substantiated that the expression of MMP-2 and MMP-9 mRNA in HAb18G/CD 147-expressing t3T3 cell was significantly greater than that in 3T3 cells. Experiments investigating adhesion potentials demonstrated that HAb18G/CD147-expressing t3T3 cells pretreated with Ca2+ attached to Matrigel-coated culture plates significantly less efficiently than 3T3 cells. The proportion of attached cells could be increased by treatment with 8-bromo-cGMP and SNAP in 3T3 cells, but not in t3T3. These results suggest that HAb18G/CD147 attenuates adhesion potentials in fibroblasts by enhancing the secretion of MMP through NO/cGMP-sensitive capacitative Ca2+ entry.
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Affiliation(s)
- Yong Huang
- Cell Engineering Research Centre & Department of Cell Biology, The Fourth Military Medical University, Xi'an 710032, PR China
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46
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Barth AS, Merk S, Arnoldi E, Zwermann L, Kloos P, Gebauer M, Steinmeyer K, Bleich M, Kääb S, Hinterseer M, Kartmann H, Kreuzer E, Dugas M, Steinbeck G, Nabauer M. Reprogramming of the Human Atrial Transcriptome in Permanent Atrial Fibrillation. Circ Res 2005; 96:1022-9. [PMID: 15817885 DOI: 10.1161/01.res.0000165480.82737.33] [Citation(s) in RCA: 154] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether reexpression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression in patients with sinus rhythm and to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed downregulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile, and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent upregulation of transcripts involved in metabolic activities, suggesting an adaptive response to increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were 5 times more likely to be upregulated in atrial fibrillation (174 genes upregulated, 35 genes downregulated), whereas atrial-specific transcripts were predominantly downregulated (56 genes upregulated, 564 genes downregulated). Overall, in fibrillating atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be upregulated (eg, metabolic processes), whereas functional classes predominantly expressed in atrial myocardium were downregulated (eg, signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium.
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Affiliation(s)
- Andreas S Barth
- Department of Medicine I, University Hospital Grosshadern, Munich, Germany.
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Goette A, Lendeckel U, Klein HU. [Molecular biology of the heart atrium. New insights into the pathophysiology of atrial fibrillation as well as its clinical implications]. ACTA ACUST UNITED AC 2005; 93:864-77. [PMID: 15568146 DOI: 10.1007/s00392-004-0147-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2004] [Accepted: 07/13/2004] [Indexed: 10/26/2022]
Abstract
Atrial fibrillation (AF) is the most common clinical arrhythmia and one of the most important factors for embolic stroke. In recent years, a tremendous amount has been learned about the pathophysiology and molecular biology of AF. Thus, pharmacologic interference with specific signal transduction pathways appears promising as a novel antiarrhythmic approach to maintain sinus rhythm and to prevent atrial clot formation. This review highlights the underlying molecular biology of atrial fibrillation, which may also be relevant for AF therapy.
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Affiliation(s)
- A Goette
- Otto-von-Guericke-Universitätsklinik Magdeburg, Klinik für Kardiologie, Angiologie und Pneumologie, Leipziger Str. 44, 39120 Magdeburg, Germany.
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48
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Kim NH, Ahn Y, Oh SK, Cho JK, Park HW, Kim YS, Hong MH, Nam KI, Park WJ, Jeong MH, Ahn BH, Choi JB, Kook H, Park JC, Jeong JW, Kang JC. Altered Patterns of Gene Expression in Response to Chronic Atrial Fibrillation. Int Heart J 2005; 46:383-95. [PMID: 16043935 DOI: 10.1536/ihj.46.383] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
To obtain greater insight into atrial remodeling at the molecular level we analyzed the changes in gene expression in human atrial tissue between patients with chronic atrial fibrillation (AF) and those with normal sinus rhythm (NSR). cDNA microarray analysis was used to identify genes differentially expressed during sustained AF of more than 6 months (n = 9, mean age, 45 +/- 12, 6 males and 3 females) as compared to those with NSR (n = 9, mean age, 47 +/- 13, 6 males and 3 females). Western blot analysis was performed to confirm the altered gene expression and to establish the changes in protein expression. DNA gel electrophoresis to establish DNA ladder formation, which was associated with apoptosis in response to chronic AF, was performed. Microscopic findings were observed via electron microscopy. In the microarray analysis, out of 8,167 candidate genes, 66 genes showed a significant change in the expression level in the patients with chronic AF, which was in contrast to those with NSR. Among those, 31 genes were consistently down-regulated and 35 up-regulated more than 2-fold. The relative amounts of the Bcl-2 and p27 in the atrial tissue were decreased and angiotensin II type 2 (AT2) receptor and p21 were increased in the patients with chronic AF as compared to those with NSR. The atrial cardiomyocytes in chronic AF showed a prominent DNA ladder, which is a biochemical hallmark of apoptosis. The expression of Bcl-2, AT2 receptor, p21, and p27 were consistent with a significant role in the apoptosis of cardiac myocytes in the patients with chronic AF.
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Affiliation(s)
- Nam-Ho Kim
- Department of Internal Medicine, Wonkwang University Hospital, Iksan, South Korea
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Hirayama Y, Atarashi H, Kobayashi Y, Horie T, Iwasaki Y, Maruyama M, Miyauchi Y, Ohara T, Yashima M, Takano T. Angiotensin-Converting Enzyme Inhibitor Therapy Inhibits the Progression From Paroxysmal Atrial Fibrillation to Chronic Atrial Fibrillation. Circ J 2005; 69:671-6. [PMID: 15914944 DOI: 10.1253/circj.69.671] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Atrial fibrillation is a progressive disease, which in the paroxysmal form (PAF) becomes more frequent and finally becomes chronic (CAF). A retrospective analysis of patients with PAF was conducted to examine the hypothesis that angiotensin-converting enzyme inhibitors (ACEI) will prevent the progression to CAF. METHODS AND RESULTS On the basis of their treatment, 95 patients with PAF were divided into 2 groups: 42 patients treated with ACEI for hypertension throughout the period of treatment and follow-up (ACEI group) and 53 patients not given ACEI (non-ACEI group). Cardiac rhythms were assessed either from the medical records or the electrocardiograms recorded every 2-4 weeks at follow-up visits. The mean follow-up time was 8.3+/-3.5 years. There was no significant difference in the use of antiarrhythmic drugs, left atrial diameter or left ventricular ejection fraction between the 2 groups. The Kaplan-Meier curve for the time to occurrence of CAF showed a lower incidence of CAF in the ACEI group and demonstrated that the 5-year probability for persistence of PAF without progression to CAF was 88.3%, but 47.5% in the non-ACEI group. CONCLUSIONS These results indicate that ACEI will prevent progression from PAF to CAF.
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Affiliation(s)
- Yoshiyuki Hirayama
- First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
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50
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Pacifico A, Henry PD. Ablation for atrial fibrillation: are cures really achieved? J Am Coll Cardiol 2004; 43:1940-2. [PMID: 15172394 DOI: 10.1016/j.jacc.2004.02.043] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2003] [Revised: 01/16/2004] [Accepted: 02/03/2004] [Indexed: 11/22/2022]
Abstract
During the past 10 years numerous studies on the treatment of paroxysmal atrial fibrillation (AF) by right and left atrial ablation procedures have been published. The results of studies based on follow-up periods of a few months have been repeatedly interpreted as providing evidence for curative therapy. However, insufficient focus on the variability of the natural history of paroxysmal AF, the inadequate detection of silent arrhythmic events, the eclectic post-interventional use of antiarrhythmic drugs, and the lack of appropriate control groups make the reports unconvincing. Randomized controlled trials are needed to confirm postulated long-term cure rates for AF.
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