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Xiang X, Mao J, Tang D, Huang H, Tang H. The ZBTB family in cardiac development and diseases. Biochem Biophys Res Commun 2025; 771:152026. [PMID: 40398093 DOI: 10.1016/j.bbrc.2025.152026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/17/2025] [Accepted: 05/14/2025] [Indexed: 05/23/2025]
Abstract
ZBTB (zinc finger and BTB domain) proteins are a class of evolutionarily conserved transcriptional factors (TFs) with zinc finger (ZF) and BTB (Broad-complex, Tram-track, and Bric-à-brac) domains. The ZBTB protein family has a wide range of functions in numerous biological processes, including cell cycle regulation, DNA repair, organ development, and haematopoietic stem cell fate determination. The ZBTB proteins regulate gene expression through interactions with transcriptional regulators, influencing processes such as myocardial contractility, inflammation, fibrosis, and cellular metabolism. Given the critical role of the ZBTB family in cardiac biology, the present review endeavours to comprehensively summarize the regulatory roles of seven ZBTB family members (HIC2, BCL6, PLZF, ZBTB17, ZBTB20, ZBTB7a, and ZBTB11) in cardiac development and diseases, along with their potential molecular mechanisms. Elucidating the molecular mechanisms of ZBTB proteins opens avenues for developing targeted therapies for cardiovascular diseases, including hypertrophy, fibrosis, and inflammation. This review provides a comprehensive summary of recent research on the role of ZBTB proteins in regulating cardiac transcription. Particular emphasis is placed on elucidating their functions in both cardiac development and the pathogenesis of cardiac diseases.
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Affiliation(s)
- Xing Xiang
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China; Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, China; Institute of Cardiovascular Disease, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jie Mao
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, China; Institute of Cardiovascular Disease, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China; School of Pharmacy, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, Hunan, 421001, China
| | - Dan Tang
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China; Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, China; Institute of Cardiovascular Disease, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Hong Huang
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, China; Institute of Cardiovascular Disease, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
| | - Huifang Tang
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, China; Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, China; Institute of Cardiovascular Disease, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
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Dahlen S, Mohanty I, Sun B, Nallapaneni S, Osei‐Owusu P. Germline deletion of Rgs2 and/or Rgs5 in male mice does not exacerbate left ventricular remodeling induced by subchronic isoproterenol infusion. Physiol Rep 2025; 13:e70178. [PMID: 39746869 PMCID: PMC11695115 DOI: 10.14814/phy2.70178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/04/2025] Open
Abstract
Sympathoexcitation is a hallmark of heart failure, with sustained β-adrenergic receptor (βAR)-G protein signaling activation. βAR signaling is modulated by regulator of G protein signaling (RGS) proteins. Previously, we reported that Gαi/o regulation by RGS2 or RGS5 is key to ventricular rhythm regulation, while the dual loss of both RGS proteins results in left ventricular (LV) dilatation and dysfunction. Here, we tested whether sustained βAR stimulation with isoproterenol (ISO, 30 mg/kg/day, 3 days) exacerbates LV remodeling in male mice with germline deletion of Rgs2 and/or Rgs5. Rgs2 KO and Rgs2/5 dbKO mice showed LV dilatation at baseline, which was unchanged by ISO. Rgs2 or Rgs5 deletion decreased Rgs1 expression, whereas Rgs5 deletion increased Rgs4 expression. ISO induced cardiac hypertrophy and interstitial fibrosis in Rgs2/5 dbKO mice without increasing cardiomyocyte size or LV dilation but increased expression of cardiac fetal gene Nppa, α-actinin, and Ca2+-/calmodulin-dependent kinase II. Single Rgs2 and Rgs5 KO mice had markedly increased CD45+ cells, whereas tissue from Rgs5 KO mice showed increased CD68+ cells, as revealed by immunohistochemistry. The results together indicate that ventricular remodeling due to Rgs2 and/or Rgs5 deletion is associated with augmented myocardial immune cell presence but is not exacerbated by sustained βAR stimulation.
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Affiliation(s)
- Shelby Dahlen
- Department of Physiology & BiophysicsCase Western Reserve University School of MedicineClevelandOhioUSA
| | - Ipsita Mohanty
- Department of Pharmacology & PhysiologyDrexel University College of MedicinePhiladelphiaPennsylvaniaUSA
| | - Bo Sun
- Department of Physiology & BiophysicsCase Western Reserve University School of MedicineClevelandOhioUSA
| | - Sanjana Nallapaneni
- Department of Physiology & BiophysicsCase Western Reserve University School of MedicineClevelandOhioUSA
| | - Patrick Osei‐Owusu
- Department of Physiology & BiophysicsCase Western Reserve University School of MedicineClevelandOhioUSA
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Posta E, Fekete I, Varkonyi I, Zold E, Barta Z. The Versatile Role of Peroxisome Proliferator-Activated Receptors in Immune-Mediated Intestinal Diseases. Cells 2024; 13:1688. [PMID: 39451206 PMCID: PMC11505700 DOI: 10.3390/cells13201688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 10/26/2024] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that sense lipophilic molecules and act as transcription factors to regulate target genes. PPARs have been implicated in the regulation of innate immunity, glucose and lipid metabolism, cell proliferation, wound healing, and fibrotic processes. Some synthetic PPAR ligands are promising molecules for the treatment of inflammatory and fibrotic processes in immune-mediated intestinal diseases. Some of these are currently undergoing or have previously undergone clinical trials. Dietary PPAR ligands and changes in microbiota composition could modulate PPARs' activation to reduce inflammatory responses in these immune-mediated diseases, based on animal models and clinical trials. This narrative review aims to summarize the role of PPARs in immune-mediated bowel diseases and their potential therapeutic use.
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Affiliation(s)
- Edit Posta
- GI Unit, Department of Infectology, Faculty of Medicine, University of Debrecen, Bartok Bela Street 2-26, 4031 Debrecen, Hungary; (I.V.); (Z.B.)
| | - Istvan Fekete
- Institute of Food Technology, Faculty of Agricultural and Food Sciences and Environmental Management, University of Debrecen, Böszörményi út 138, 4032 Debrecen, Hungary;
| | - Istvan Varkonyi
- GI Unit, Department of Infectology, Faculty of Medicine, University of Debrecen, Bartok Bela Street 2-26, 4031 Debrecen, Hungary; (I.V.); (Z.B.)
| | - Eva Zold
- Department of Clinical Immunology, Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, Móricz Zsigmond str. 22, 4032 Debrecen, Hungary;
| | - Zsolt Barta
- GI Unit, Department of Infectology, Faculty of Medicine, University of Debrecen, Bartok Bela Street 2-26, 4031 Debrecen, Hungary; (I.V.); (Z.B.)
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Skoczyńska A, Ołdakowska M, Dobosz A, Adamiec R, Gritskevich S, Jonkisz A, Lebioda A, Adamiec-Mroczek J, Małodobra-Mazur M, Dobosz T. PPARs in Clinical Experimental Medicine after 35 Years of Worldwide Scientific Investigations and Medical Experiments. Biomolecules 2024; 14:786. [PMID: 39062500 PMCID: PMC11275227 DOI: 10.3390/biom14070786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
This year marks the 35th anniversary of Professor Walter Wahli's discovery of the PPARs (Peroxisome Proliferator-Activated Receptors) family of nuclear hormone receptors. To mark the occasion, the editors of the scientific periodical Biomolecules decided to publish a special issue in his honor. This paper summarizes what is known about PPARs and shows how trends have changed and how research on PPARs has evolved. The article also highlights the importance of PPARs and what role they play in various diseases and ailments. The paper is in a mixed form; essentially it is a review article, but it has been enriched with the results of our experiments. The selection of works was subjective, as there are more than 200,000 publications in the PubMed database alone. First, all papers done on an animal model were discarded at the outset. What remained was still far too large to describe directly. Therefore, only papers that were outstanding, groundbreaking, or simply interesting were described and briefly commented on.
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Affiliation(s)
- Anna Skoczyńska
- Department of Internal and Occupational Medicine and Hypertension, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Monika Ołdakowska
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Agnieszka Dobosz
- Department of Basic Medical Sciences and Immunology, Division of Basic Medical Sciences, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland
| | - Rajmund Adamiec
- Department of Diabetology and Internal Medicine, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
- Department of Internal Medicine, Faculty of Medical and Technical Sciences, Karkonosze University of Applied Sciences, Lwówiecka 18, 58-506 Jelenia Góra, Poland
| | - Sofya Gritskevich
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Anna Jonkisz
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Arleta Lebioda
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Joanna Adamiec-Mroczek
- Department of Ophthalmology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Małgorzata Małodobra-Mazur
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Tadeusz Dobosz
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
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Kumar K, Rawat P, Kaur S, Singh N, Yadav HN, Singh D, Jaggi AS, Sethi D. Unveiling Wide Spectrum Therapeutic Implications and Signaling Mechanisms of Valsartan in Diverse Disorders: A Comprehensive Review. Curr Drug Res Rev 2024; 16:268-288. [PMID: 37461345 DOI: 10.2174/2589977515666230717120828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/27/2023] [Accepted: 08/24/2023] [Indexed: 09/04/2024]
Abstract
Valsartan is an orally active non-peptide angiotensin receptor antagonist, an effective and well-tolerated anti-hypertensive drug. Besides its antihypertensive action, it has clinical implications in many other disorders, like heart failure (HF), arrhythmia, chronic kidney disease (CKD), diabetic complications (DM), atherosclerosis, etc. Besides angiotensin receptor blocking activity, valsartan reduces circulating levels of biochemical markers, such as hs-CRP, which is responsible for its anti-inflammatory and anti-oxidant activity. Moreover, valsartan also acts by inhibiting or inducing various signalling pathways, such as inducing autophagy via the AKT/mTOR/S6K pathway or inhibiting the TLR/NF-kB pathway. The current review exhaustively discusses the therapeutic implications of valsartan with specific emphasis on the mechanism of action in various disorders. The article provides a detailed spectrum of the therapeutic profile of valsartan and will likely be very useful to researchers working in the relevant research areas.
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Affiliation(s)
- Kuldeep Kumar
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Pooja Rawat
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Simrat Kaur
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Nirmal Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Harlokesh Narayan Yadav
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Dhandeep Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Amteshwar Singh Jaggi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Dimple Sethi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
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Kong P, Wang X, Gao YK, Zhang DD, Huang XF, Song Y, Zhang WD, Guo RJ, Li H, Han M. RGS5 maintaining vascular homeostasis is altered by the tumor microenvironment. Biol Direct 2023; 18:78. [PMID: 37986113 PMCID: PMC10662775 DOI: 10.1186/s13062-023-00437-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 11/05/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Regulator of G protein signaling 5 (RGS5), as a negative regulator of G protein-coupled receptor (GPCR) signaling, is highly expressed in arterial VSMCs and pericytes, which is involved in VSMC phenotypic heterogeneity and vascular remodeling in tumors. However, its role in normal and tumor vascular remodeling is controversial. METHODS RGS5 knockout (Rgs5-KO) mice and RGS5 overexpression or knockdown in VSMCs in vivo by adeno-associated virus type 9 (AAV) carrying RGS5 cDNA or small hairpin RNA (shRNA) targeting RGS5 were used to determine the functional significance of RGS5 in vascular inflammation. RGS5 expression in the triple-negative (TNBCs) and non-triple-negative breast cancers (Non-TNBCs) was determined by immunofluorescent and immunohistochemical staining. The effect of breast cancer cell-conditioned media (BC-CM) on the pro-inflammatory phenotype of VSMCs was measured by phagocytic activity assays, adhesion assay and Western blot. RESULTS We identified that knockout and VSMC-specific knockdown of RGS5 exacerbated accumulation and pyroptosis of pro-inflammatory VSMCs, resulting in vascular remodeling, which was negated by VSMC-specific RGS5 overexpression. In contrast, in the context of breast cancer tissues, the role of RGS5 was completely disrupted. RGS5 expression was increased in the triple-negative breast cancer (TNBC) tissues and in the tumor blood vessels, accompanied with an extensive vascular network. VSMCs treated with BC-CM displayed enhanced pro-inflammatory phenotype and higher adherent with macrophages. Furthermore, tumor-derived RGS5 could be transferred into VSMCs. CONCLUSIONS These findings suggest that tumor microenvironment shifts the function of RGS5 from anti-inflammation to pro-inflammation and induces the pro-inflammatory phenotype of VSMCs that is favorable for tumor metastasis.
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Affiliation(s)
- Peng Kong
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Xu Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Hebei Medical University, Shijiazhuang, China
| | - Ya-Kun Gao
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Dan-Dan Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Xiao-Fu Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Yu Song
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Wen-Di Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Rui-Juan Guo
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Han Li
- Department of Orthopaedic Surgery, Institute of Biomechanical Science and Biomechanical Key Laboratory of Hebei Province, Third Hospital of Hebei Medical University, Shijiazhuang, China.
| | - Mei Han
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China.
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Yin S, Ma XY, Sun YF, Yin YQ, Long Y, Zhao CL, Ma JW, Li S, Hu Y, Li MT, Hu G, Zhou JW. RGS5 augments astrocyte activation and facilitates neuroinflammation via TNF signaling. J Neuroinflammation 2023; 20:203. [PMID: 37674228 PMCID: PMC10481574 DOI: 10.1186/s12974-023-02884-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 08/28/2023] [Indexed: 09/08/2023] Open
Abstract
Astrocytes contribute to chronic neuroinflammation in a variety of neurodegenerative diseases, including Parkinson's disease (PD), the most common movement disorder. However, the precise role of astrocytes in neuroinflammation remains incompletely understood. Herein, we show that regulator of G-protein signaling 5 (RGS5) promotes neurodegenerative process through augmenting astrocytic tumor necrosis factor receptor (TNFR) signaling. We found that selective ablation of Rgs5 in astrocytes caused an inhibition in the production of cytokines resulting in mitigated neuroinflammatory response and neuronal survival in animal models of PD, whereas overexpression of Rgs5 had the opposite effects. Mechanistically, RGS5 switched astrocytes from neuroprotective to pro-inflammatory property via binding to the receptor TNFR2. RGS5 also augmented TNFR signaling-mediated pro-inflammatory response by interacting with the receptor TNFR1. Moreover, interrupting RGS5/TNFR interaction by either RGS5 aa 1-108 or small molecular compounds feshurin and butein, suppressed astrocytic cytokine production. We showed that the transcription of astrocytic RGS5 was controlled by transcription factor early B cell factor 1 whose expression was reciprocally influenced by RGS5-modulated TNF signaling. Thus, our study indicates that beyond its traditional role in G-protein coupled receptor signaling, astrocytic RGS5 is a key modulator of TNF signaling circuit with resultant activation of astrocytes thereby contributing to chronic neuroinflammation. Blockade of the astrocytic RGS5/TNFR interaction is a potential therapeutic strategy for neuroinflammation-associated neurodegenerative diseases.
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Affiliation(s)
- Shu Yin
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Intelligence Technology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Xin-Yue Ma
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Ying-Feng Sun
- Center for Brain Disorders Research, Center of Parkinson's Disease, Capital Medical University, Beijing Institute for Brain Disorders, Beijing, 100053, China
| | - Yan-Qing Yin
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Intelligence Technology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Ying Long
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Chun-Lai Zhao
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Intelligence Technology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Jun-Wei Ma
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Sen Li
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Intelligence Technology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Yan Hu
- Guangdong Provincial Key Laboratory of Brain Function, Disease, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Ming-Tao Li
- Guangdong Provincial Key Laboratory of Brain Function, Disease, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Gang Hu
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
| | - Jia-Wei Zhou
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Intelligence Technology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
- School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China.
- Shanghai Center for Brain Science, Brain-Inspired Intelligence Technology, Shanghai, 201210, China.
- Co-Innovation Center of Neuroregeneration, School of Medicine, Nantong University, Nantong, 226001, Jiangsu, China.
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Kato T, Fukao K, Ohara T, Naya N, Tokuyama R, Muto S, Fukasawa H, Itai A, Matsumura KI. Design, Synthesis, and Anti-Inflammatory Evaluation of a Novel PPARδ Agonist with a 4-(1-Pyrrolidinyl)piperidine Structure. J Med Chem 2023; 66:11428-11446. [PMID: 37552807 DOI: 10.1021/acs.jmedchem.3c00932] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a pharmaceutical target to treat metabolic diseases including atherosclerosis, but there is no PPARδ agonist available for clinical use. We have previously reported the discovery of piperidinyl/piperazinyl benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening methods. In the present study, we found that introduction of a pyrrolidine group into the 4-position of their central piperidine rings enhances hPPARδ activity and subtype selectivity. This led to the discovery of 21 having strong PPARδ agonist activity (EC50 = 3.6 nM) with excellent ADME properties. Furthermore, 21 significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.
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Affiliation(s)
- Terukazu Kato
- Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan
| | - Keita Fukao
- Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan
| | - Takafumi Ohara
- Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan
| | - Noriyuki Naya
- Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan
| | - Ryukou Tokuyama
- Institute of Medicinal Molecular Design, Inc., Tokyo 113-0033, Japan
| | - Susumu Muto
- Institute of Medicinal Molecular Design, Inc., Tokyo 113-0033, Japan
| | - Hiroshi Fukasawa
- Institute of Medicinal Molecular Design, Inc., Tokyo 113-0033, Japan
| | - Akiko Itai
- Institute of Medicinal Molecular Design, Inc., Tokyo 113-0033, Japan
| | - Ken-Ichi Matsumura
- Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan
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Miao M, Wang X, Liu T, Li YJ, Yu WQ, Yang TM, Guo SD. Targeting PPARs for therapy of atherosclerosis: A review. Int J Biol Macromol 2023:125008. [PMID: 37217063 DOI: 10.1016/j.ijbiomac.2023.125008] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 05/24/2023]
Abstract
Atherosclerosis, a chief pathogenic factor of cardiovascular disease, is associated with many factors including inflammation, dyslipidemia, and oxidative stress. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are widely expressed with tissue- and cell-specificity. They control multiple genes that are involved in lipid metabolism, inflammatory response, and redox homeostasis. Given the diverse biological functions of PPARs, they have been extensively studied since their discovery in 1990s. Although controversies exist, accumulating evidence have demonstrated that PPAR activation attenuates atherosclerosis. Recent advances are valuable for understanding the mechanisms of action of PPAR activation. This article reviews the recent findings, mainly from the year of 2018 to present, including endogenous molecules in regulation of PPARs, roles of PPARs in atherosclerosis by focusing on lipid metabolism, inflammation, and oxidative stress, and synthesized PPAR modulators. This article provides information valuable for researchers in the field of basic cardiovascular research, for pharmacologists that are interested in developing novel PPAR agonists and antagonists with lower side effects as well as for clinicians.
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Affiliation(s)
- Miao Miao
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Xue Wang
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Tian Liu
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Yan-Jie Li
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Wen-Qian Yu
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Tong-Mei Yang
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Shou-Dong Guo
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China.
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10
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Wu C, Chen Y, Zhou P, Hu Z. Recombinant human angiotensin-converting enzyme 2 plays a protective role in mice with sepsis-induced cardiac dysfunction through multiple signaling pathways dependent on converting angiotensin II to angiotensin 1-7. ANNALS OF TRANSLATIONAL MEDICINE 2023; 11:13. [PMID: 36760245 PMCID: PMC9906207 DOI: 10.21037/atm-22-6016] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/29/2022] [Indexed: 01/13/2023]
Abstract
Background Sepsis-induced cardiac dysfunction (SICD) is a common complication of sepsis and contributes to mortality and the complexity of management in patients with sepsis. Recombinant human angiotensin-converting enzyme 2 (rhACE2) has been reported to protect the heart from injury and dysfunction in conditions which involve increased angiotensin II (Ang II). In this study, we aimed to detect the effects of rhACE2 on SICD. Methods A SICD model was developed in male C57/B6 mice by lipopolysaccharide (LPS) intraperitoneal injection. When cardiac dysfunction was confirmed by echocardiography 3 hours after LPS administration, mice were treated with either saline, rhACE2, or rhACE2 + A779. All mice received echocardiographic examination at 6 hours after LPS injection and then were sacrificed for serum and myocardial tissues collection. Angiotensin, cardiac troponin I (cTnI), and inflammatory markers in serum were measured. Histopathology features were examined by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining to evaluate structure injury and cell pyroptosis rate in heart tissue respectively. Pyroptosis-related proteins and signaling pathways involved in nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in heart tissue were investigated by western blot (WB). Results RhACE2 relieved myocardial injury and improved cardiac function in mice with SICD accompanied by decrease of Ang II and increase of angiotensin 1-7 (Ang 1-7) in serum. RhACE2 diminished activation of NLRP3 inflammasome, inflammatory response, and cell pyroptosis induced by LPS. In addition, rhACE2 partly inhibited activation of nuclear factor κB (NF-κB), the p38 mitogen-activated protein kinase (MAPK) pathway, and promoted activation of the AMP-activated protein kinase-α1 (AMPK-α1) pathway in heart tissue. Administration of A779 offset the inhibitive effects of rhACE2 on NLRP3 expression and protective role on cardiac injury and dysfunction in mice with SICD. Conclusions RhACE2 plays a protective role in SICD, ameliorating cardiac injury and dysfunction through NF-κB, p38 MAPK, and the AMPK-α1/NLRP3 inflammasome pathway dependent on converting Ang II to Ang 1-7.
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Affiliation(s)
- Chunxue Wu
- Department of Critical Care Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China;,Intensive Care Unit of Emergency Department, Neurology Branch of Cangzhou Central Hospital, Cangzhou, China;,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, China
| | - Yuhong Chen
- Department of Critical Care Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China;,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, China
| | - Pan Zhou
- Department of Critical Care Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China;,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, China
| | - Zhenjie Hu
- Department of Critical Care Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China;,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, China
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11
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Kim B, Lee CJ, Won HH, Lee SH. Genetic Variants Associated with Supernormal Coronary Arteries. J Atheroscler Thromb 2022; 30:467-480. [PMID: 35793981 PMCID: PMC10164599 DOI: 10.5551/jat.63554] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
AIMS Genetic and medical insights from studies on cardioprotective phenotypes aid the development of novel therapeutics. This study identified genetic variants associated with supernormal coronary arteries using genome-wide association study data and the corresponding genes based on expression quantitative trait loci (eQTL). METHODS Study participants were selected from two Korean cohorts according to inclusion criteria that included males with high cardiovascular risk (Framingham risk score ≥ 14, 10-year risk ≥ 16%) but with normal coronary arteries (supernormal group) or coronary artery disease (control group). After screening 12,309 individuals, males meeting the supernormal phenotype (n=72) and age-matched controls (n=94) were enrolled. Genetic variants associated with the supernormal phenotype were identified using Firth's logistic regression, and eQTL was used to evaluate whether the identified variants influence the expression of particular genes in human tissues. RESULTS Approximately 5 million autosomal variants were tested for association with the supernormal phenotype, and 10 independent loci suggestive of supernormal coronary arteries (p＜5.0 ×10 －5) were identified. The lead variants were seven intergenic single-nucleotide polymorphisms (SNPs), including one near PBX1, and three intronic SNPs, including one in PPFIA4. Of these variants or their proxies, rs9630089, rs6427989, and rs4984694 were associated with expression levels of SLIT1 and ARHGAP19, PPFIA4, and METTL26 in human tissues, respectively. These eQTL results supported their potential biological relevance. CONCLUSIONS This study identified genetic variants and eQTL genes associated with supernormal coronary arteries. These results suggest candidate genes representing potential therapeutic targets for coronary artery disease.
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Affiliation(s)
- Beomsu Kim
- Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center
| | - Chan Joo Lee
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine
| | - Hong-Hee Won
- Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center
| | - Sang-Hak Lee
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine
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12
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Xiao L, Wang N. PPAR-δ: A key nuclear receptor in vascular function and remodeling. J Mol Cell Cardiol 2022; 169:1-9. [DOI: 10.1016/j.yjmcc.2022.04.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/29/2022] [Accepted: 04/25/2022] [Indexed: 12/08/2022]
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13
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A regulator of G protein signaling 5 marked subpopulation of vascular smooth muscle cells is lost during vascular disease. PLoS One 2022; 17:e0265132. [PMID: 35320283 PMCID: PMC8942229 DOI: 10.1371/journal.pone.0265132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/23/2022] [Indexed: 11/19/2022] Open
Abstract
Vascular smooth muscle cell (VSMC) subpopulations relevant to vascular disease and injury repair have been depicted in healthy vessels and atherosclerosis profiles. However, whether VSMC subpopulation associated with vascular homeostasis exists in the healthy artery and how are their nature and fate in vascular remodeling remains elusive. Here, using single-cell RNA-sequencing (scRNA-seq) to detect VSMC functional heterogeneity in an unbiased manner, we showed that VSMC subpopulations in healthy artery presented transcriptome diversity and that there was significant heterogeneity in differentiation state and development within each subpopulation. Notably, we detected an independent subpopulation of VSMCs that highly expressed regulator of G protein signaling 5 (RGS5), upregulated the genes associated with inhibition of cell proliferation and construction of cytoskeleton compared with the general subpopulation, and mainly enriched in descending aorta. Additionally, the proportion of RGS5high VSMCs was markedly decreased or almost disappeared in the vascular tissues of neointimal formation, abdominal aortic aneurysm and atherosclerosis. Specific spatiotemporal characterization of RGS5high VSMC subpopulation suggested that this subpopulation was implicated in vascular homeostasis. Together, our analyses identify homeostasis-relevant transcriptional signatures of VSMC subpopulations in healthy artery, which may explain the regional vascular resistance to atherosclerosis at some extent.
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14
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Xu L, Wu J, Liu Y, Chen G, Ma C, Zhang H. Peroxisome proliferator‑activated receptor β/δ regulates cerebral vasospasm after subarachnoid hemorrhage via modulating vascular smooth muscle cells phenotypic conversion. Mol Med Rep 2021; 24:860. [PMID: 34664679 PMCID: PMC8548938 DOI: 10.3892/mmr.2021.12500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 09/27/2021] [Indexed: 11/06/2022] Open
Abstract
Cerebral vasospasm (CVS) is a common complication of subarachnoid hemorrhage (SAH) with high deformity rates and cerebral vascular smooth muscle cells (VSMCs) phenotypic switch is considered to be involved in the regulation of CVS. However, to the best of the authors' knowledge, its underlying molecular mechanism remains to be elucidated. Peroxisome proliferator‑activated receptor β/δ (PPARβ/δ) has been demonstrated to be involved in the modulation of vascular cells proliferation and maintains the autoregulation function of blood vessels. The present study investigated the potential effect of PPARβ/δ on CVS following SAH. A model of SAH was established by endovascular perforation on male adult Sprague‑Dawley rats, and the adenovirus PPARβ/δ (Ad‑PPARβ/δ) was injected via intracerebroventricular administration prior to SAH. The expression levels of phenotypic markers α‑smooth muscle actin and embryonic smooth muscle myosin heavy chain were measured via western blotting or immunofluorescence staining. The basilar artery diameter and vessel wall thickness were evaluated under fluorescence microscopy. SAH grade, neurological scores, brain water content and brain swelling were measured to study the mechanisms of PPARβ/δ on vascular smooth muscle phenotypic transformation. It was revealed that the expression levels of synthetic proteins were upregulated in rats with SAH and this was accompanied by CVS. Activation of PPARβ/δ using Ad‑PPARβ/δ markedly upregulated the contractile proteins elevation, restrained the synthetic proteins expression and attenuated SAH‑induced CVS by regulating the phenotypic switch in VSMCs at 72 h following SAH. Furthermore, the preliminary study demonstrated that PPARβ/δ downregulated ERK activity and decreased the expression of phosphorylated (p‑)ETS domain‑containing protein Elk‑1 and p‑p90 ribosomal S6 kinase, which have been demonstrated to serve an important role in VSMC phenotypic change. Additionally, it was revealed that Ad‑PPARβ/δ could positively improve CVS by ameliorating the diameter of the basilar artery and mitigating the thickness of the vascular wall. Furthermore, subsequent experiments demonstrated that Ad‑PPARβ/δ markedly reduced the brain water content and brain swelling and improved the neurological outcome. Taken together, the present study identified PPARβ/δ as a useful regulator for the VSMCs phenotypic switch and attenuating CVS following SAH, thereby providing novel insights into the therapeutic strategies of delayed cerebral ischemia.
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Affiliation(s)
- Li Xu
- Intensive Care Unit of Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215026, P.R. China
| | - Jiang Wu
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215026, P.R. China
| | - Yuan Liu
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215026, P.R. China
| | - Gang Chen
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215026, P.R. China
| | - Chao Ma
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215026, P.R. China
| | - Hongrong Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215026, P.R. China
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15
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Gene Doping with Peroxisome-Proliferator-Activated Receptor Beta/Delta Agonists Alters Immunity but Exercise Training Mitigates the Detection of Effects in Blood Samples. Int J Mol Sci 2021; 22:ijms222111497. [PMID: 34768927 PMCID: PMC8584242 DOI: 10.3390/ijms222111497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/22/2021] [Accepted: 10/23/2021] [Indexed: 12/17/2022] Open
Abstract
Synthetic ligands of peroxisome-proliferator-activated receptor beta/delta (PPARβ/δ) are being used as performance-enhancing drugs by athletes. Since we previously showed that PPARβ/δ activation affects T cell biology, we wanted to investigate whether a specific blood T cell signature could be employed as a method to detect the use of PPARβ/δ agonists. We analyzed in primary human T cells the in vitro effect of PPARβ/δ activation on fatty acid oxidation (FAO) and on their differentiation into regulatory T cells (Tregs). Furthermore, we conducted studies in mice assigned to groups according to an 8-week exercise training program and/or a 6-week treatment with 3 mg/kg/day of GW0742, a PPARβ/δ agonist, in order to (1) determine the immune impact of the treatment on secondary lymphoid organs and to (2) validate a blood signature. Our results show that PPARβ/δ activation increases FAO potential in human and mouse T cells and mouse secondary lymphoid organs. This was accompanied by increased Treg polarization of human primary T cells. Moreover, Treg prevalence in mouse lymph nodes was increased when PPARβ/δ activation was combined with exercise training. Lastly, PPARβ/δ activation increased FAO potential in mouse blood T cells. Unfortunately, this signature was masked by training in mice. In conclusion, beyond the fact that it is unlikely that this signature could be used as a doping-control strategy, our results suggest that the use of PPARβ/δ agonists could have potential detrimental immune effects that may not be detectable in blood samples.
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16
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Adhikari UK, Sakiz E, Zhou X, Habiba U, Kumar S, Mikhael M, Senesi M, Guang Li C, Guillemin GJ, Ooi L, David MA, Collins S, Karl T, Tayebi M. Cross-Linking Cellular Prion Protein Induces Neuronal Type 2-Like Hypersensitivity. Front Immunol 2021; 12:639008. [PMID: 34394070 PMCID: PMC8361482 DOI: 10.3389/fimmu.2021.639008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 07/13/2021] [Indexed: 01/13/2023] Open
Abstract
Background Previous reports identified proteins associated with ‘apoptosis’ following cross-linking PrPC with motif-specific anti-PrP antibodies in vivo and in vitro. The molecular mechanisms underlying this IgG-mediated neurotoxicity and the role of the activated proteins in the apoptotic pathways leading to neuronal death has not been properly defined. Previous reports implicated a number of proteins, including apolipoprotein E, cytoplasmic phospholipase A2, prostaglandin and calpain with anti-PrP antibody-mediated ‘apoptosis’, however, these proteins are also known to play an important role in allergy. In this study, we investigated whether cross-linking PrPC with anti-PrP antibodies stimulates a neuronal allergenic response. Methods Initially, we predicted the allergenicity of the epitope sequences associated with ‘neurotoxic’ anti-PrP antibodies using allergenicity prediction servers. We then investigated whether anti-PrP antibody treatment of mouse primary neurons (MPN), neuroblastoma cells (N2a) and microglia (N11) cell lines lead to a neuronal allergenic response. Results In-Silico studies showed that both tail- and globular-epitopes were allergenic. Specifically, binding regions that contain epitopes for previously reported ‘neurotoxic’ antibodies such as ICSM18 (146-159), ICSM35 (91-110), POM 1 (138-147) and POM 3 (95-100) lead to activation of allergenic related proteins. Following direct application of anti-PrPC antibodies on N2a cells, we identified 4 neuronal allergenic-related proteins when compared with untreated cells. Furthermore, we identified 8 neuronal allergenic-related proteins following treatment of N11 cells with anti-PrPC antibodies prior to co-culture with N2a cells when compared with untreated cells. Antibody treatment of MPN or MPN co-cultured with antibody-treated N11 led to identifying 10 and 7 allergenic-related proteins when compared with untreated cells. However, comparison with 3F4 antibody treatment revealed 5 and 4 allergenic-related proteins respectively. Of importance, we showed that the allergenic effects triggered by the anti-PrP antibodies were more potent when antibody-treated microglia were co-cultured with the neuroblastoma cell line. Finally, co-culture of N2a or MPN with N11-treated with anti-PrP antibodies resulted in significant accumulation of NO and IL6 but not TNF-α in the cell culture media supernatant. Conclusions This study showed for the first time that anti-PrP antibody binding to PrPC triggers a neuronal hypersensitivity response and highlights the important role of microglia in triggering an IgG-mediated neuronal hypersensitivity response. Moreover, this study provides an important impetus for including allergenic assessment of therapeutic antibodies for neurodegenerative disorders to derive safe and targeted biotherapeutics.
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Affiliation(s)
| | - Elif Sakiz
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Xian Zhou
- National Institute of Complementary Medicine (NICM) Health Research Institute, Western Sydney University, Campbelltown, NSW, Australia
| | - Umma Habiba
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Sachin Kumar
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Meena Mikhael
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Matteo Senesi
- Australian National Creutzfeldt-Jakob Disease Registry, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia
| | - Chun Guang Li
- National Institute of Complementary Medicine (NICM) Health Research Institute, Western Sydney University, Campbelltown, NSW, Australia
| | - Gilles J Guillemin
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Wollongong, NSW, Australia
| | - Lezanne Ooi
- School of Chemistry and Molecular Bioscience, Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.,School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
| | | | - Steven Collins
- Australian National Creutzfeldt-Jakob Disease Registry, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia
| | - Tim Karl
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia.,Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia.,School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Mourad Tayebi
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
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17
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Hwang JS, Hur J, Lee WJ, Won JP, Lee HG, Lim DS, Kim E, Seo HG. Catalase Mediates the Inhibitory Actions of PPARδ against Angiotensin II-Triggered Hypertrophy in H9c2 Cardiomyocytes. Antioxidants (Basel) 2021; 10:antiox10081223. [PMID: 34439471 PMCID: PMC8388952 DOI: 10.3390/antiox10081223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 01/05/2023] Open
Abstract
Hypertrophy of myocytes has been implicated in cardiac dysfunctions affecting wall stress and patterns of gene expression. However, molecular targets potentially preventing cardiac hypertrophy have not been fully elucidated. In the present study, we demonstrate that upregulation of catalase by peroxisome proliferator-activated receptor δ (PPARδ) is involved in the anti-hypertrophic activity of PPARδ in angiotensin II (Ang II)-treated H9c2 cardiomyocytes. Activation of PPARδ by a specific ligand GW501516 significantly inhibited Ang II-induced hypertrophy and the generation of reactive oxygen species (ROS) in H9c2 cardiomyocytes. These effects of GW501516 were almost completely abolished in cells stably expressing small hairpin (sh)RNA targeting PPARδ, indicating that PPARδ mediates these effects. Significant concentration and time-dependent increases in catalase at both mRNA and protein levels were observed in GW501516-treated H9c2 cardiomyocytes. In addition, GW501516-activated PPARδ significantly enhanced catalase promoter activity and protein expression, even in the presence of Ang II. GW501516-activated PPARδ also inhibited the expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which are both marker proteins for hypertrophy. The effects of GW501516 on the expression of ANP and BNP were reversed by 3-amino-1,2,4-triazole (3-AT), a catalase inhibitor. Inhibition or downregulation of catalase by 3-AT or small interfering (si)RNA, respectively, abrogated the effects of PPARδ on Ang II-induced hypertrophy and ROS generation, indicating that these effects of PPARδ are mediated through catalase induction. Furthermore, GW501516-activated PPARδ exerted catalase-dependent inhibitory effects on Ang II-induced hypertrophy by blocking p38 mitogen-activated protein kinase. Taken together, these results indicate that the anti-hypertrophic activity of PPARδ may be achieved, at least in part, by sequestering ROS through fine-tuning the expression of catalase in cardiomyocytes.
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Affiliation(s)
- Jung Seok Hwang
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Jinwoo Hur
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Won Jin Lee
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Jun Pil Won
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Hyuk Gyoon Lee
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Dae-Seog Lim
- Department of Biotechnology, CHA University, 355 Pangyo-ro, Bundang-gu, Seongnam 13488, Korea;
| | - Eunsu Kim
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
| | - Han Geuk Seo
- College of Sang-Huh Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (J.S.H.); (J.H.); (W.J.L.); (J.P.W.); (H.G.L.); (E.K.)
- Correspondence: ; Tel.: +82-2-450-0428; Fax: +82-2-455-1044
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18
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Paredes A, Santos-Clemente R, Ricote M. Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease. Int J Mol Sci 2021; 22:ijms22157775. [PMID: 34360540 PMCID: PMC8346021 DOI: 10.3390/ijms22157775] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/13/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022] Open
Abstract
The heart is the first organ to acquire its physiological function during development, enabling it to supply the organism with oxygen and nutrients. Given this early commitment, cardiomyocytes were traditionally considered transcriptionally stable cells fully committed to contractile function. However, growing evidence suggests that the maintenance of cardiac function in health and disease depends on transcriptional and epigenetic regulation. Several studies have revealed that the complex transcriptional alterations underlying cardiovascular disease (CVD) manifestations such as myocardial infarction and hypertrophy is mediated by cardiac retinoid X receptors (RXR) and their partners. RXRs are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and drive essential biological processes such as ion handling, mitochondrial biogenesis, and glucose and lipid metabolism. RXRs are thus attractive molecular targets for the development of effective pharmacological strategies for CVD treatment and prevention. In this review, we summarize current knowledge of RXR partnership biology in cardiac homeostasis and disease, providing an up-to-date view of the molecular mechanisms and cellular pathways that sustain cardiomyocyte physiology.
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19
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Tian Q, Leung FP, Chen FM, Tian XY, Chen Z, Tse G, Ma S, Wong WT. Butyrate protects endothelial function through PPARδ/miR-181b signaling. Pharmacol Res 2021; 169:105681. [PMID: 34019979 DOI: 10.1016/j.phrs.2021.105681] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/21/2021] [Accepted: 05/14/2021] [Indexed: 01/06/2023]
Abstract
Reports of the beneficial roles of butyrate in cardiovascular diseases, such as atherosclerosis and ischemic stroke, are becoming increasingly abundant. However, the mechanisms of its bioactivities remain largely unknown. In this study, we explored the effects of butyrate on endothelial dysfunction and its potential underlying mechanism. In our study, ApoE-/- mice were fed with high-fat diet (HFD) for ten weeks to produce atherosclerosis models and concurrently treated with or without sodium butyrate daily. Thoracic aortas were subsequently isolated from C57BL/6 wild-type (WT), PPARδ-/-, endothelial-specific PPARδ wild-type (EC-specific PPARδ WT) and endothelial-specific PPARδ knockout (EC-specific PPARδ KO) mice were stimulated with interleukin (IL)-1β with or without butyrate ex vivo. Our results demonstrated that butyrate treatment rescued the impaired endothelium-dependent relaxations (EDRs) in thoracic aortas of HFD-fed ApoE-/- mice. Butyrate also rescued impaired EDRs in IL-1β-treated thoracic aorta ring ex vivo. Global and endothelial-specific knockout of PPARδ eliminated the protective effects of butyrate against IL-1β-induced impairment to EDRs. Butyrate abolished IL-1β-induced reactive oxygen species (ROS) production in endothelial cells while the inhibitory effect was incapacitated by genetic deletion of PPARδ or pharmacological inhibition of PPARδ. IL-1β increased NADPH oxidase 2 (NOX2) mRNA and protein expressions in endothelial cells, which were prevented by butyrate treatment, and the effects of butyrate were blunted following pharmacological inhibition of PPARδ. Importantly, butyrate treatment upregulated the miR-181b expression in atherosclerotic aortas and IL-1β-treated endothelial cells. Moreover, transfection of endothelial cells with miR-181b inhibitor abolished the suppressive effects of butyrate on NOX2 expressions and ROS generation in endothelial cells. To conclude, butyrate prevents endothelial dysfunction in atherosclerosis by reducing endothelial NOX2 expression and ROS production via the PPARδ/miR-181b pathway.
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Affiliation(s)
- Qinqin Tian
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Fung Ping Leung
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Francis M Chen
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiao Yu Tian
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Zhenyu Chen
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Gary Tse
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China; Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Shuangtao Ma
- Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MICH, USA
| | - Wing Tak Wong
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China; State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.
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Yan Q, Tang J, Zhang X, Wu L, Xu Y, Wang L. Does Transient Receptor Potential Vanilloid Type 1 Alleviate or Aggravate Pathological Myocardial Hypertrophy? Front Pharmacol 2021; 12:681286. [PMID: 34040539 PMCID: PMC8143375 DOI: 10.3389/fphar.2021.681286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 04/27/2021] [Indexed: 12/21/2022] Open
Abstract
Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel, which is involved in the endogenous stress adaptation mechanism for protection of the heart as well as the occurrence and development of some heart diseases. Although the effect of activation of the TRPV1 channel on different types of non-neural cells in the heart remains unclear, most data show that stimulation of sensory nerves expressing TRPV1 or stimulation/overexpression of the TRPV1 channel has a beneficial role in heart disease. Some studies have proven that TRPV1 has an important relationship with pathological myocardial hypertrophy, but the specific mechanism and effect are not clear. In order to help researchers better understand the relationship between TRPV1 and pathological myocardial hypertrophy, this paper aims to summarize the effect of TRPV1 and the related mechanism in the occurrence and development of pathological myocardial hypertrophy from the following three points of view: 1) role of TRPV1 in alleviation of pathological myocardial hypertrophy; 2) role of TRPV1 in aggravation of pathological myocardial hypertrophy; and 3) the point of view of our team of researchers. It is expected that new therapies can provide potential targets for pathological myocardial hypertrophy.
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Affiliation(s)
- Qiqi Yan
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Jun Tang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xin Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Liuyang Wu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Yunyi Xu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Lihong Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
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21
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Wang J, Ma J, Nie H, Zhang XJ, Zhang P, She ZG, Li H, Ji YX, Cai J. Hepatic Regulator of G Protein Signaling 5 Ameliorates Nonalcoholic Fatty Liver Disease by Suppressing Transforming Growth Factor Beta-Activated Kinase 1-c-Jun-N-Terminal Kinase/p38 Signaling. Hepatology 2021; 73:104-125. [PMID: 32191345 DOI: 10.1002/hep.31242] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 03/02/2020] [Accepted: 03/04/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, which has no specific pharmacological treatments partially because of the unclear pathophysiological mechanisms. Regulator of G protein signaling (RGSs) proteins are proteins that negatively regulate G protein-coupled receptor (GPCR) signaling. The members of the R4/B subfamily are the smallest RGS proteins in size, and RGS5 belongs to this family, which mediates pluripotent biological functions through canonical G protein-mediated pathways and non-GPCR pathways. This study combined a genetically engineered rodent model and a transcriptomics-sequencing approach to investigate the role and regulatory mechanism of RGS5 in the development of NAFLD. APPROACH AND RESULTS This study found that RGS5 protects against NAFLD and nonalcoholic steatohepatitis. Using RNA sequencing and an unbiased systematic investigative approach, this study found that the activation of mitogen-activated protein kinase signaling cascades in response to metabolic challenge is negatively associated with hepatic RGS5 expression. Mechanistically, we found that the 64-181 amino-acid-sequence (aa) fragment of RGS5 directly interacts with transforming growth factor beta-activated kinase 1 (TAK1) through the 1-300aa fragment and inhibits TAK1 phosphorylation and the subsequent c-Jun-N-terminal kinase (JNK)/p38 pathway activation. CONCLUSIONS In hepatocytes, RGS5 is an essential molecule that protects against the progression of NAFLD. RGS5 directly binds to TAK1, preventing its hyperphosphorylation and the activation of the downstream JNK/p38 signaling cascade. RGS5 is a promising target molecule for fine-tuning the activity of TAK1 and for the treatment of NAFLD.
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Affiliation(s)
- Junyong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Medical Research Institute, Wuhan University, Wuhan, China
| | - Junpeng Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Basic Medical School, Wuhan University, Wuhan, China
| | - Hongyu Nie
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Basic Medical School, Wuhan University, Wuhan, China
| | - Xiao-Jing Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Basic Medical School, Wuhan University, Wuhan, China
| | - Peng Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Basic Medical School, Wuhan University, Wuhan, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Basic Medical School, Wuhan University, Wuhan, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Basic Medical School, Wuhan University, Wuhan, China
| | - Yan-Xiao Ji
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Basic Medical School, Wuhan University, Wuhan, China
- Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jingjing Cai
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
- Department of Cardiology, Central South University, The Third Xiangya Hospital, Changsha, China
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22
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Geiger MA, Guillaumon AT, Paneni F, Matter CM, Stein S. Role of the Nuclear Receptor Corepressor 1 (NCOR1) in Atherosclerosis and Associated Immunometabolic Diseases. Front Immunol 2020; 11:569358. [PMID: 33117357 PMCID: PMC7578257 DOI: 10.3389/fimmu.2020.569358] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/24/2020] [Indexed: 11/13/2022] Open
Abstract
Atherosclerotic cardiovascular disease is part of chronic immunometabolic disorders such as type 2 diabetes and nonalcoholic fatty liver disease. Their common risk factors comprise hypertension, insulin resistance, visceral obesity, and dyslipidemias, such as hypercholesterolemia and hypertriglyceridemia, which are part of the metabolic syndrome. Immunometabolic diseases include chronic pathologies that are affected by both metabolic and inflammatory triggers and mediators. Important and challenging questions in this context are to reveal how metabolic triggers and their downstream signaling affect inflammatory processes and vice-versa. Along these lines, specific nuclear receptors sense changes in lipid metabolism and in turn induce downstream inflammatory and metabolic processes. The transcriptional activity of these nuclear receptors is regulated by the nuclear receptor corepressors (NCORs), including NCOR1. In this review we describe the function of NCOR1 as a central immunometabolic regulator and focus on its role in atherosclerosis and associated immunometabolic diseases.
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Affiliation(s)
- Martin A Geiger
- Vascular Diseases Discipline, Clinics Hospital of the University of Campinas, Campinas, Brazil
| | - Ana T Guillaumon
- Vascular Diseases Discipline, Clinics Hospital of the University of Campinas, Campinas, Brazil
| | - Francesco Paneni
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.,Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland.,Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
| | - Christian M Matter
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.,Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
| | - Sokrates Stein
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.,Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
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23
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Imanaka-Yoshida K, Tawara I, Yoshida T. Tenascin-C in cardiac disease: a sophisticated controller of inflammation, repair, and fibrosis. Am J Physiol Cell Physiol 2020; 319:C781-C796. [PMID: 32845719 DOI: 10.1152/ajpcell.00353.2020] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Tenascin-C (TNC) is a large extracellular matrix glycoprotein classified as a matricellular protein that is generally upregulated at high levels during physiological and pathological tissue remodeling and is involved in important biological signaling pathways. In the heart, TNC is transiently expressed at several important steps during embryonic development and is sparsely detected in normal adult heart but is re-expressed in a spatiotemporally restricted manner under pathological conditions associated with inflammation, such as myocardial infarction, hypertensive cardiac fibrosis, myocarditis, dilated cardiomyopathy, and Kawasaki disease. Despite its characteristic and spatiotemporally restricted expression, TNC knockout mice develop a grossly normal phenotype. However, various disease models using TNC null mice combined with in vitro experiments have revealed many important functions for TNC and multiple molecular cascades that control cellular responses in inflammation, tissue repair, and even myocardial regeneration. TNC has context-dependent diverse functions and, thus, may exert both harmful and beneficial effects in damaged hearts. However, TNC appears to deteriorate adverse ventricular remodeling by proinflammatory and profibrotic effects in most cases. Its specific expression also makes TNC a feasible diagnostic biomarker and target for molecular imaging to assess inflammation in the heart. Several preclinical studies have shown the utility of TNC as a biomarker for assessing the prognosis of patients and selecting appropriate therapy, particularly for inflammatory heart diseases.
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Affiliation(s)
- Kyoko Imanaka-Yoshida
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.,Mie University Research Center for Matrix Biology, Tsu, Japan
| | - Isao Tawara
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.,Mie University Research Center for Matrix Biology, Tsu, Japan
| | - Toshimichi Yoshida
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.,Mie University Research Center for Matrix Biology, Tsu, Japan
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24
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The Emerging Role of PPAR Beta/Delta in Tumor Angiogenesis. PPAR Res 2020; 2020:3608315. [PMID: 32855630 PMCID: PMC7443046 DOI: 10.1155/2020/3608315] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 07/24/2020] [Indexed: 12/31/2022] Open
Abstract
PPARs are ligand-activated transcriptional factors that belong to the nuclear receptor superfamily. Among them, PPAR alpha and PPAR gamma are prone to exert an antiangiogenic effect, whereas PPAR beta/delta has an opposite effect in physiological and pathological conditions. Angiogenesis has been known as a hallmark of cancer, and our recent works also demonstrate that vascular-specific PPAR beta/delta overexpression promotes tumor angiogenesis and progression in vivo. In this review, we will mainly focus on the role of PPAR beta/delta in tumor angiogenesis linked to the tumor microenvironment to further facilitate tumor progression and metastasis. Moreover, the crosstalk between PPAR beta/delta and its downstream key signal molecules involved in tumor angiogenesis will also be discussed, and the network of interplay between them will further be established in the review.
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Peroxisome Proliferator-Activated Receptor Beta/Delta Agonist Suppresses Inflammation and Promotes Neovascularization. Int J Mol Sci 2020; 21:ijms21155296. [PMID: 32722564 PMCID: PMC7432070 DOI: 10.3390/ijms21155296] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/20/2020] [Accepted: 07/23/2020] [Indexed: 01/10/2023] Open
Abstract
The effects of peroxisome proliferator-activated receptor (PPAR)β/δ ophthalmic solution were investigated in a rat corneal alkali burn model. After alkali injury, GW501516 (PPARβ/δ agonist) or vehicle ophthalmic solution was topically instilled onto the rat’s cornea twice a day until day 7. Pathological findings were evaluated, and real-time reverse transcription polymerase chain reaction was performed. GW501516 strongly suppressed infiltration of neutrophils and pan-macrophages, and reduced the mRNA expression of interleukin-6, interleukin-1β, tumor necrosis factor alpha, and nuclear factor-kappa B. On the other hand, GW501516 promoted infiltration of M2 macrophages, infiltration of vascular endothelial cells associated with neovascularization in the wounded area, and expression of vascular endothelial growth factor A mRNA. However, 7-day administration of GW501516 did not promote neovascularization in uninjured normal corneas. Thus, the PPARβ/δ ligand suppressed inflammation and promoted neovascularization in the corneal wound healing process. These results will help to elucidate the role of PPARβ/δ in the field of ophthalmology.
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Peroxisome proliferator-activated receptor β/δ and γ agonists differentially affect prostaglandin E2 and cytokine synthesis and nutrient transporter expression in porcine trophoblast cells during implantation. Theriogenology 2020; 152:36-46. [PMID: 32361305 DOI: 10.1016/j.theriogenology.2020.04.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 03/24/2020] [Accepted: 04/18/2020] [Indexed: 01/09/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor family of ligand-dependent transcription factors. PPARs have been shown to be important regulators of female reproductive functions, including conceptus development and placenta formation. This study examines the effect of PPARβ/δ and PPARγ agonists and antagonists on (1) the synthesis of prostaglandin (PG) E2, interleukin (IL) 6, interferon (IFN) γ, and tumor necrosis factor (TNF) α and (2) the mRNA expression of genes encoding nutrient transporters and/or binding proteins in Day 15 conceptus trophoblast cells. The study also examines whether PPAR agonist-modulated IL6, IFNγ, and TNFα secretion is mediated via mitogen-activated protein kinase (MAPK) pathways. Trophoblast cells were exposed to L-165,041 (a PPARβ/δ agonist) or rosiglitazone (a PPARγ agonist) in the presence or absence of GSK3787 (a PPARβ/δ antagonist) or GW9662 (a PPARγ antagonist) or in the presence or absence of U0126 (a MAPK inhibitor). Rosiglitazone stimulated PGE synthase and IFNG mRNA expression in trophoblast cells and enhanced PGE2 concentrations in the incubation medium. Moreover, cells treated with rosiglitazone exhibited increased abundance of the solute carrier organic anion transporter family member 2A1 (SLCO2A1, a PG transporter) and of fatty acid binding protein (FABP) 5 transcripts. All these effects were abolished by the addition of GW9662, which indicates that the action of rosiglitazone is PPARγ-dependent in the studied cells. L-165,041 inhibited TNFα synthesis and decreased the mRNA expression of FABP3 and IL6 in trophoblast cells. However, this effect was not abolished by the addition of GSK3787 into the incubation medium, suggesting that L-165,041 action is independent of PPARβ/δ. The inhibitory effect of L-165,041 on TNFα concentration and the stimulatory effect of rosiglitazone on IFNγ accumulation in the medium were not observed in the presence of the MAPK inhibitor, suggesting that the action of both agonists may be mediated by MAPKs. In conclusion, PPARβ/δ and PPARγ agonists are differentially involved in the trophoblast expression of genes related to conceptus development and implantation in pigs. Furthermore, L-165,041 and rosiglitazone may have PPAR-dependent and -independent effects in conceptus trophoblast cells.
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27
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Tian D, Hong H, Shang W, Ho CC, Dong J, Tian XY. Deletion of Ppard in CD11c + cells attenuates atherosclerosis in ApoE knockout mice. FASEB J 2020; 34:3367-3378. [PMID: 31919912 DOI: 10.1096/fj.201902069r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 12/13/2019] [Accepted: 12/27/2019] [Indexed: 12/14/2022]
Abstract
Ppardδ, one of the lipid-activated nuclear receptor expressed in many cell types to activate gene transcription, also regulates cellular functions other than lipid metabolism. The mechanism regulating the function of antigen-presenting cells during the development of atherosclerosis is not fully understood. Here we aimed to study the involvement of PPARδ in CD11c+ cells in atherosclerosis. We used the Cre-loxP approach to make conditional deletion of Ppard in CD11c+ cells in mice on Apoe-/- background, which were fed with high cholesterol diet to develop atherosclerosis. Ppard deficiency in CD11c+ cells attenuated atherosclerotic plaque formation and infiltration of myeloid-derived dendritic cells (DCs) and T lymphocytes. Reduced lesion was accompanied by reduced activation of dendritic cells, and also a reduction of activation and differentiation of T cells to Th1 cells. In addition, DC migration to lymph node was also attenuated with Ppard deletion. In bone marrow-derived DCs, Ppard deficiency reduced palmitic acid-induced upregulation of co-stimulatory molecules and pro-inflammatory cytokine IL12 and TNFα. Our results indicated PPARδ activation by fatty acid resulted in the activation of myeloid DCs and subsequent polarization of T lymphocytes, which contributed to atherosclerosis in Apoe-/- mice. These findings also reveal the potential regulatory role of PPARδ in antigen presentation to orchestrate the immune responses during atherosclerosis.
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Affiliation(s)
- Danyang Tian
- School of Biomedical Sciences, Institute of Vascular Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong.,Department of Physiology, Hebei Medical University, Shijiazhuang, China
| | - Huiling Hong
- School of Biomedical Sciences, Institute of Vascular Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
| | - Wenbin Shang
- School of Biomedical Sciences, Institute of Vascular Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
| | - Chin Chung Ho
- School of Biomedical Sciences, Institute of Vascular Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
| | - Jinghui Dong
- Department of Physiology, Hebei Medical University, Shijiazhuang, China
| | - Xiao Yu Tian
- School of Biomedical Sciences, Institute of Vascular Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
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28
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Hydrogen sulfide improves endothelial dysfunction in hypertension by activating peroxisome proliferator-activated receptor delta/endothelial nitric oxide synthase signaling. J Hypertens 2019; 36:651-665. [PMID: 29084084 DOI: 10.1097/hjh.0000000000001605] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE We aimed to elucidate the ameliorative effect of hydrogen sulfide (H2S) on endothelium-dependent relaxation disturbances via peroxisome proliferator-activated receptor delta/endothelial nitric oxide synthase (PPARδ/eNOS) pathway activation in hypertensive patients and rats. METHODS Renal arteries were collected from normotensive and hypertensive patients who underwent nephron-sparing surgery. Renal arteries from 37 patients were cultured with or without sodium H2S (NaHS) 50 μmol/l. The rats were randomly divided into four groups: Sham; Sham + NaHS, two kidneys; one clipped (2K1C); and 2K1C + NaHS. Mean arterial pressure was measured by tail-cuff plethysmography. A microvessel recording technique was used to observe the effect of NaHS on endothelium-dependent relaxation. Plasma H2S concentrations were detected using the monobromobimane method. Real-time PCR and western blotting were used to assess mRNA and protein levels of AT1, cystathionine γ-lyase, PPARδ, and phosphor-eNOS. Laser confocal scanning microscopy measured intracellular NO production in human umbilical vein endothelial cells. RESULTS NaHS improved endothelial function in hypertensive humans and rats. The 20-week administration of NaHS to 2K1C rats lowered the mean arterial pressure. In human umbilical vein endothelial cells, NaHS improved the AngII-induced production of NO. NaHS upregulated PPARδ expression, increased protein kinase B (Akt) or adenosine monophosphate kinase-activated protein kinase (AMPK) phosphorylation, and enhanced eNOS phosphorylation. A PPARδ agonist could mimic the ameliorative effect of NaHS that was suppressed by PPARδ, AMPK, or Akt inhibition. CONCLUSION H2S plays a protective function in renal arterial endothelium in hypertension by activating the PPARδ/PI3K/Akt/eNOS or PPARδ/AMPK/eNOS pathway. H2S may serve as an effective strategy against hypertension.
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PPARγ Agonist PGZ Attenuates OVA-Induced Airway Inflammation and Airway Remodeling via RGS4 Signaling in Mouse Model. Inflammation 2019; 41:2079-2089. [PMID: 30022363 DOI: 10.1007/s10753-018-0851-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone (PGZ) exhibits potential protective effects in asthma. Recently, regulator of G protein 4 (RGS4) has been reported to be associated with immunological and inflammatory responses. However, no evidence has shown the influence of PPARγ on RGS4 expression in airway disorders. In this study, BALB/c mice received ovalbumin (OVA) sensitization followed by OVA intranasal challenge for 90 days to establish a chronic asthma mouse model. Accompanied with OVA challenge, the mice received administration of PPARγ agonist PGZ (10 mg/kg) intragastrically or RGS4 inhibitor CCG 63802 (0.5 mg/kg) intratracheally. Invasive pulmonary function tests were performed 24 h after last challenge. Serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for further analyses after the mice were sacrificed. We found that PPARγ agonist PGZ administration significantly attenuated the pathophysiological features of OVA-induced asthma and increased the expression of RGS4. In addition, the attenuating effect of PGZ on airway inflammation, hyperresponsiveness (AHR), and remodeling was partially abrogated by administration of RGS4 inhibitor CCG 63802. We also found that the downregulation of RGS4 by CCG 63802 also significantly increased inflammatory cell accumulation and AHR, and increased levels of IL-4, IL-13, eotaxin, IFN-γ, and IL-17A in BALF, and total and OV-specific IgE in serum. Furthermore, the inhibitory effects of PGZ on the activations of ERK and Akt/mTOR signaling, and MMPs were apparently reversed by CCG 63802 administration. In conclusion, the protective effect of PGZ on OVA-induced airway inflammation and remodeling might be partly regulated by RGS4 expression through ERK and Akt/mTOR signaling.
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Aster glehni Extract Containing Caffeoylquinic Compounds Protects Human Keratinocytes through the TRPV4-PPAR δ-AMPK Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2018:9616574. [PMID: 30622619 PMCID: PMC6304624 DOI: 10.1155/2018/9616574] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 10/21/2018] [Accepted: 11/12/2018] [Indexed: 11/17/2022]
Abstract
Aster glehni (AG) has been used in cooking and as a medicine to treat various diseases for over hundreds of years in Korea. To speculate the protective effects of AG on skin barrier, we estimated the protein levels of biomarkers related to skin barrier protection in human keratinocytes, HaCaT cells treated with sodium dodecyl sulfate (SDS), or 2,4-dinitrochlorobenzene (DNCB). The protein levels for keratin, involucrin, defensin, tumor necrosis factor alpha (TNFα), peroxisome proliferator-activated receptor delta (PPARδ), 5′ adenosine monophosphate-activated protein kinase (AMPK), serine palmitoyltransferase long chain base subunit 2 (SPTLC2), and transient receptor potential cation channel subfamily V member 4 (TRPV4) were evaluated using western blotting or immunocytochemistry in HaCaT cells. AG extract increased the protein levels of PPARδ, phosphorylated AMPK, SPTLC2, keratin, involucrin, and defensin compared to the SDS or DNCB control group. However, TNFα expression increased by SDS or DNCB was decreased with AG extract. The order of action of each regulatory biomarker in AG pathway was identified TRPV4→PPARδ→AMPK from antagonist and siRNA treatment studies. AG can ameliorate the injury of keratinocytes caused by SDS or DNCB through the sequential regulation of TRPV4→PPARδ→AMPK pathway.
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31
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Kang ES, Hwang JS, Lee WJ, Lee GH, Choi MJ, Paek KS, Lim DS, Seo HG. Ligand-activated PPARδ inhibits angiotensin II-stimulated hypertrophy of vascular smooth muscle cells by targeting ROS. PLoS One 2019; 14:e0210482. [PMID: 30620754 PMCID: PMC6324793 DOI: 10.1371/journal.pone.0210482] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 12/25/2018] [Indexed: 11/19/2022] Open
Abstract
We investigated the effect of peroxisome proliferator-activated receptor δ (PPARδ) on angiotensin II (Ang II)-triggered hypertrophy of vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand of PPARδ, significantly inhibited Ang II-stimulated protein synthesis in a concentration-dependent manner, as determined by [3H]-leucine incorporation. GW501516-activated PPARδ also suppressed Ang II-induced generation of reactive oxygen species (ROS) in VSMCs. Transfection of small interfering RNA (siRNA) against PPARδ significantly reversed the effects of GW501516 on [3H]-leucine incorporation and ROS generation, indicating that PPARδ is involved in these effects. By contrast, these GW501516-mediated actions were potentiated in VSMCs transfected with siRNA against NADPH oxidase (NOX) 1 or 4, suggesting that ligand-activated PPARδ elicits these effects by modulating NOX-mediated ROS generation. The phosphatidylinositol 3-kinase inhibitor LY294002 also inhibited Ang II-stimulated [3H]-leucine incorporation and ROS generation by preventing membrane translocation of Rac1. These observations suggest that PPARδ is an endogenous modulator of Ang II-triggered hypertrophy of VSMCs, and is thus a potential target to treat vascular diseases associated with hypertrophic changes of VSMCs.
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Affiliation(s)
- Eun Sil Kang
- College of Sang-Huh Life Sciences, Konkuk University, Gwangjin-gu, Seoul, Korea
| | - Jung Seok Hwang
- College of Sang-Huh Life Sciences, Konkuk University, Gwangjin-gu, Seoul, Korea
| | - Won Jin Lee
- College of Sang-Huh Life Sciences, Konkuk University, Gwangjin-gu, Seoul, Korea
| | - Gyeong Hee Lee
- College of Sang-Huh Life Sciences, Konkuk University, Gwangjin-gu, Seoul, Korea
| | - Mi-Jung Choi
- College of Sang-Huh Life Sciences, Konkuk University, Gwangjin-gu, Seoul, Korea
| | | | - Dae-Seog Lim
- Department of Biotechnology, CHA University, Bundang-gu, Seongnam, Korea
| | - Han Geuk Seo
- College of Sang-Huh Life Sciences, Konkuk University, Gwangjin-gu, Seoul, Korea
- * E-mail:
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32
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A partial agonist for retinoid X receptor mitigates experimental colitis. Int Immunol 2018; 31:251-262. [DOI: 10.1093/intimm/dxy089] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 12/24/2018] [Indexed: 12/14/2022] Open
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33
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Forrester SJ, Booz GW, Sigmund CD, Coffman TM, Kawai T, Rizzo V, Scalia R, Eguchi S. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol Rev 2018; 98:1627-1738. [PMID: 29873596 DOI: 10.1152/physrev.00038.2017] [Citation(s) in RCA: 727] [Impact Index Per Article: 103.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (AT1R) is believed to mediate most functions of ANG II in the system. AT1R utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between AT1R signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. AT1R remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.
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Affiliation(s)
- Steven J Forrester
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - George W Booz
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Curt D Sigmund
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Thomas M Coffman
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Tatsuo Kawai
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Victor Rizzo
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Rosario Scalia
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Satoru Eguchi
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
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Abstract
The nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) can transcriptionally regulate target genes. PPARδ exerts essential regulatory functions in the heart, which requires constant energy supply. PPARδ plays a key role in energy metabolism, controlling not only fatty acid (FA) and glucose oxidation, but also redox homeostasis, mitochondrial biogenesis, inflammation, and cardiomyocyte proliferation. PPARδ signaling is impaired in the heart under various pathological conditions, such as pathological cardiac hypertrophy, myocardial ischemia/reperfusion, doxorubicin cardiotoxicity and diabetic cardiomyopathy. PPARδ deficiency in the heart leads to cardiac dysfunction, myocardial lipid accumulation, cardiac hypertrophy/remodeling and heart failure. This article provides an up-today overview of this research area and discusses the role of PPARδ in the heart in light of the complex mechanisms of its transcriptional regulation and its potential as a translatable therapeutic target for the treatment of cardiac disorders.
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Affiliation(s)
- Qinglin Yang
- Cardiovascular Center of Excellence, LSU Healther Science Center, 533 Bolivar St, New Orleans, LA 70112, USA
| | - Qinqiang Long
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
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35
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Heck BE, Park JJ, Makani V, Kim EC, Kim DH. PPAR-δ Agonist With Mesenchymal Stem Cells Induces Type II Collagen-Producing Chondrocytes in Human Arthritic Synovial Fluid. Cell Transplant 2018; 26:1405-1417. [PMID: 28901183 PMCID: PMC5680970 DOI: 10.1177/0963689717720278] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Osteoarthritis (OA) is an inflammatory joint disease characterized by degeneration of articular cartilage within synovial joints. An estimated 27 million Americans suffer from OA, and the population is expected to reach 67 million in the United States by 2030. Thus, it is urgent to find an effective treatment for OA. Traditional OA treatments have no disease-modifying effect, while regenerative OA therapies such as autologous chondrocyte implantation show some promise. Nonetheless, current regenerative therapies do not overcome synovial inflammation that suppresses the differentiation of mesenchymal stem cells (MSCs) to chondrocytes and the expression of type II collagen, the major constituent of functional cartilage. We discovered a synergistic combination that overcame synovial inflammation to form type II collagen-producing chondrocytes. The combination consists of peroxisome proliferator–activated receptor (PPAR) δ agonist, human bone marrow (hBM)-derived MSCs, and hyaluronic acid (HA) gel. Interestingly, those individual components showed their own strong enhancing effects on chondrogenesis. GW0742, a PPAR-δ agonist, greatly enhanced MSC chondrogenesis and the expression of type II collagen and glycosaminoglycan (GAG) in hBM-MSC-derived chondrocytes. GW0742 also increased the expression of transforming growth factor β that enhances chondrogenesis and suppresses cartilage fibrillation, ossification, and inflammation. HA gel also increased MSC chondrogenesis and GAG production. However, neither GW0742 nor HA gel could enhance the formation of type II collagen-producing chondrocytes from hBM-MSCs within human OA synovial fluid. Our data demonstrated that the combination of hBM-MSCs, PPAR-δ agonist, and HA gel significantly enhanced the formation of type II collagen-producing chondrocytes within OA synovial fluid from 3 different donors. In other words, the novel combination of PPAR-δ agonist, hBM-MSCs, and HA gel can overcome synovial inflammation to form type II collagen cartilage within human OA synovial fluid. This novel articularly injectable formula could improve OA treatment in the future clinical application.
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Affiliation(s)
- Bruce E Heck
- 1 NWO Stem Cure, LLC, Findlay, OH, USA.,2 Northwest Ohio Orthopedics and Sports Medicine, Findlay, OH, USA
| | - Joshua J Park
- 3 Department of Neurosciences, University of Toledo College of Medicine and Life Science, Toledo, OH, USA
| | - Vishruti Makani
- 3 Department of Neurosciences, University of Toledo College of Medicine and Life Science, Toledo, OH, USA
| | - Eun-Cheol Kim
- 4 Department of Oral and Maxillofacial Pathology, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea
| | - Dong Hyun Kim
- 1 NWO Stem Cure, LLC, Findlay, OH, USA.,2 Northwest Ohio Orthopedics and Sports Medicine, Findlay, OH, USA.,5 Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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36
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Luo F, Shi J, Shi Q, He X, Xia Y. ERK and p38 Upregulation versus Bcl-6 Downregulation in Rat Kidney Epithelial Cells Exposed to Prolonged Hypoxia. Cell Transplant 2018; 26:1441-1451. [PMID: 28901193 PMCID: PMC5680977 DOI: 10.1177/0963689717720296] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Hypoxia is a common cause of kidney injury and a major issue in kidney transplantation. Mitogen-activated protein kinases (MAPKs) are involved in the cellular response to hypoxia, but the precise roles of MAPKs in renal cell reactions to hypoxic stress are not well known yet. This work was conducted to investigate the regulation of extracellular signal-regulated kinase-1 and -2 (ERK1/2) and p38 and their signaling-relevant molecules in kidney epithelial cells exposed to prolonged hypoxia. Rat kidney epithelial cells Normal Rat Kidney (NRK)-52E were exposed to hypoxic conditions (1% O2) for 24 to 72 h. Cell morphology was examined by light microscopy, and cell viability was checked by 3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxypheny]-2-[4-sulfophenyl]-2H-tetrazolium (MTS). The expression of ERK1/2 and p38 MAPK, as well as their signaling-related molecules, was measured by Western blot and real-time polymerase chain (RT-PCR) reaction. At the 1% oxygen level, cell morphology had no appreciable changes compared to the control up to 72 h of exposure under light microscopy, whereas the results of MTS showed a slight but significant reduction in cell viability after 72 h of hypoxia. On the other hand, ERK1/2 and p38 phosphorylation remarkably increased in these cells after 24 to 72 h of hypoxia. In sharp contrast, the expression of transcription factor B-cell lymphoma 6 (Bcl-6) was significantly downregulated in response to hypoxic stress. Other intracellular molecules relevant to the ERK1/2 and p38 signaling pathway, such as protein kinase A, protein kinase C, Bcl-2, nuclear factor erythroid 2-related factor 2, tristetraprolin, and interleukin-10(IL-10), had no significant alterations after 24 to 72 h of hypoxic exposure. We conclude that hypoxic stress increases the phosphorylation of both ERK1/2 and p38 but decreases the level of Bcl-6 in rat kidney epithelial cells.
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Affiliation(s)
- Fengbao Luo
- 1 Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Jian Shi
- 1 Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Qianqian Shi
- 1 Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Xiaozhou He
- 1 Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Ying Xia
- 2 Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
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37
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Busch D, Kapoor A, Rademann P, Hildebrand F, Bahrami S, Thiemermann C, Osuchowski MF. Delayed activation of PPAR-β/δ improves long-term survival in mouse sepsis: effects on organ inflammation and coagulation. Innate Immun 2018; 24:262-273. [PMID: 29697010 DOI: 10.1177/1753425918771748] [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] [Indexed: 12/19/2022] Open
Abstract
Activation of peroxisome proliferator-activated receptor (PPAR)-β/δ reduces tissue injury in murine endotoxemia. We hypothesized that the PPAR-β/δ-agonist GW0742 improves long-term outcome after sepsis caused by cecal ligation and puncture (CLP). Fifty-one CD-1 female mice underwent CLP and received either vehicle (control), GW0742 (0.03 mg/kg/injection; five post-CLP i.v. injections), GSK0660 (PPAR-β/δ-antagonist) or both and were monitored for 28 d. Another 20 CLP mice treated with GW0742 and vehicle were sacrificed 24 h post-CLP to assess coagulopathy. Compared to vehicle, survival of CLP-mice treated with GW0742 was higher by 35% at d 7 and by 50% at d 28. CLP mice treated with GW0742 had 60% higher IFN-γ but circulating monocyte chemoattractant protein-1 and chemokine ligand were lower at 48 h post-CLP. Compared to vehicle, CLP mice treated with GW0742 exhibited a 50% reduction in the circulating plasminogen activator inhibitor-1 associated with an increase in platelet number at 24 h post-CLP (but no changes occurred in anti-thrombin-III, plasminogen, fibrinogen and clotting-times). CLP mice treated with GW0742 exhibited a similar increase in most of the biochemical markers of organ injury/dysfunction (lactate dehydrogenase, alanine aminotransferase, creatine kinase, creatinine, blood urea nitrogen, and triglycerides) measured. Treatment with GW0742 consistently improved long-term survival in septic CD-1 mice by partially modulating the post-CLP systemic cytokine response and coagulation systems.
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Affiliation(s)
- Daniel Busch
- 1 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria.,2 Department of General-, Visceral-, Thoracic- and Vascular Surgery, Helios Hanseklinikum Stralsund, Germany
| | - Amar Kapoor
- 3 Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, London, UK
| | - Pia Rademann
- 1 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria.,4 Center for Experimental Medicine, Medical Faculty, University of Cologne, Cologne, Germany
| | | | - Soheyl Bahrami
- 1 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
| | - Christoph Thiemermann
- 3 Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, London, UK
| | - Marcin F Osuchowski
- 1 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
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38
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Ahn MY, Ham SA, Yoo T, Lee WJ, Hwang JS, Paek KS, Lim DS, Han SG, Lee CH, Seo HG. Ligand-Activated Peroxisome Proliferator-Activated Receptor δ Attenuates Vascular Oxidative Stress by Inhibiting Thrombospondin-1 Expression. J Vasc Res 2018; 55:75-86. [PMID: 29408825 DOI: 10.1159/000486570] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 12/29/2017] [Indexed: 11/19/2022] Open
Abstract
Thrombospondin-1 (TSP-1) is implicated in vascular diseases associated with oxidative stress, such as abdominal aortic aneurysms, ischemia-reperfusion injury, and atherosclerosis. However, the regulatory mechanisms underlying TSP-1 expression are not fully elucidated. In this study, we found that peroxisome proliferator-activated receptor δ (PPARδ) inhibited oxidative stress-induced TSP-1 expression and migration in vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly attenuated hydrogen peroxide (H2O2)-induced expression of TSP-1 in VSMCs. Small interfering RNA-mediated knockdown of PPARδ and treatment with GSK0660, a selective PPARδ antagonist, reversed the effect of GW501516 on H2O2-induced expression of TSP-1, suggesting that PPARδ is associated with GW501516 activity. Furthermore, JNK (c-Jun N-terminal kinase), but not p38 and ERK (extracellular signal-regulated kinase), mediated PPARδ-dependent inhibition of TSP-1 expression in VSMCs exposed to H2O2. GW501516- activated PPARδ also reduced the H2O2-induced generation of reactive oxygen species, concomitant with inhibition of VSMC migration. In particular, TSP-1 contributed to the action of PPARδ in the regulation of H2O2-induced interleukin-1β expression. These results suggest that PPARδ-modulated downregulation of TSP-1 is associated with reduced cellular oxidative stress, thereby inhibiting H2O2-induced pheno-typic changes in vascular cells.
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Affiliation(s)
- Min Young Ahn
- Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea
| | - Sun Ah Ham
- Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea
| | - Taesik Yoo
- Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea
| | - Won Jin Lee
- Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea
| | - Jung Seok Hwang
- Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea
| | - Kyung Shin Paek
- Department of Nursing, Semyung University, Jechon, Republic of Korea
| | - Dae-Seog Lim
- Department of Biotechnology, CHA University, Seongnam, Republic of Korea
| | - Sung Gu Han
- Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea
| | - Chi-Ho Lee
- Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea
| | - Han Geuk Seo
- Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea
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39
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Banno A, Reddy AT, Lakshmi SP, Reddy RC. PPARs: Key Regulators of Airway Inflammation and Potential Therapeutic Targets in Asthma. NUCLEAR RECEPTOR RESEARCH 2017; 5. [PMID: 29450204 DOI: 10.11131/2018/101306] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Asthma affects approximately 300 million people worldwide, significantly impacting quality of life and healthcare costs. While current therapies are effective in controlling many patients' symptoms, a large number continue to experience exacerbations or treatment-related adverse effects. Alternative therapies are thus urgently needed. Accumulating evidence has shown that the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors, comprising PPARα, PPARβ/δ, and PPARγ, is involved in asthma pathogenesis and that ligand-induced activation of these receptors suppresses asthma pathology. PPAR agonists exert their anti-inflammatory effects primarily by suppressing pro-inflammatory mediators and antagonizing the pro-inflammatory functions of various cell types relevant to asthma pathophysiology. Experimental findings strongly support the potential clinical benefits of PPAR agonists in the treatment of asthma. We review current literature, highlighting PPARs' key role in asthma pathogenesis and their agonists' therapeutic potential. With additional research and rigorous clinical studies, PPARs may become attractive therapeutic targets in this disease.
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Affiliation(s)
- Asoka Banno
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Aravind T Reddy
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.,Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240
| | - Sowmya P Lakshmi
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.,Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240
| | - Raju C Reddy
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.,Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240
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40
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Liu C, Hu Q, Jing J, Zhang Y, Jin J, Zhang L, Mu L, Liu Y, Sun B, Zhang T, Kong Q, Wang G, Wang D, Zhang Y, Liu X, Zhao W, Wang J, Feng T, Li H. Regulator of G protein signaling 5 (RGS5) inhibits sonic hedgehog function in mouse cortical neurons. Mol Cell Neurosci 2017; 83:65-73. [PMID: 28684360 DOI: 10.1016/j.mcn.2017.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Revised: 02/21/2017] [Accepted: 06/20/2017] [Indexed: 12/12/2022] Open
Abstract
Regulator of G protein signaling 5 (RGS5) acts as a GTPase-activating protein (GAP) for the Gαi subunit and negatively regulates G protein-coupled receptor signaling. However, its presence and function in postmitotic differentiated primary neurons remains largely uncharacterized. During neural development, sonic hedgehog (Shh) signaling is involved in cell signaling pathways via Gαi activity. In particular, Shh signaling is essential for embryonic neural tube patterning, which has been implicated in neuronal polarization involving neurite outgrowth. Here, we examined whether RGS5 regulates Shh signaling in neurons. RGS5 transcripts were found to be expressed in cortical neurons and their expression gradually declined in a time-dependent manner in culture system. When an adenovirus expressing RGS5 was introduced into an in vitro cell culture model of cortical neurons, RGS5 overexpression significantly reduced neurite outgrowth and FM4-64 uptake, while cAMP-PKA signaling was also affected. These findings suggest that RGS5 inhibits Shh function during neurite outgrowth and the presynaptic terminals of primary cortical neurons mature via modulation of cAMP.
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Affiliation(s)
- Chuanliang Liu
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China; Vocational College Daxing'an Mountains, Jiagedaqi District, Heilongjiang 165000, China
| | - Qiongqiong Hu
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Jia Jing
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Yun Zhang
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Jing Jin
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Liulei Zhang
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Lili Mu
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Yumei Liu
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Bo Sun
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Tongshuai Zhang
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Qingfei Kong
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Guangyou Wang
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Dandan Wang
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Yao Zhang
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Xijun Liu
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Wei Zhao
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China
| | - Jinghua Wang
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China.
| | - Tao Feng
- Department of Neurology, The Nangang Branch of Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150001, China.
| | - Hulun Li
- Department of Neurobiology, Harbin Medical University, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin, Heilongjiang 150086, China; Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, Heilongjiang 150086, China
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41
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Druey KM. Emerging Roles of Regulators of G Protein Signaling (RGS) Proteins in the Immune System. Adv Immunol 2017; 136:315-351. [PMID: 28950950 DOI: 10.1016/bs.ai.2017.05.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Kirk M Druey
- Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, MD, United States.
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42
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Ganss R. Maternal Metabolism and Vascular Adaptation in Pregnancy: The PPAR Link. Trends Endocrinol Metab 2017; 28:73-84. [PMID: 27789100 DOI: 10.1016/j.tem.2016.09.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 09/22/2016] [Accepted: 09/23/2016] [Indexed: 12/17/2022]
Abstract
Current therapies for pregnancy-related hypertension and its complications remain inadequate, although an increasing role for maternal susceptibility is becoming evident. Systemic vascular dysfunction in response to imbalances in angiogenic, inflammatory, and constricting factors is implicated in the pathogenesis of gestational hypertension, and growing evidence now links these factors with maternal metabolism. In particular, the crucial role of peroxisome proliferator-activated receptors (PPARs) in maternal vascular adaptation provides further insights into how obesity and gestational diabetes may be linked to pregnancy-induced hypertension and preeclampsia. This is especially important given the rapidly growing prevalence of obesity during pregnancy, and highlights a new approach to treat pregnancy-related hypertension and its complications.
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Affiliation(s)
- Ruth Ganss
- Vascular Biology and Stromal Targeting, Harry Perkins Institute of Medical Research, The University of Western Australia, Centre for Medical Research, Nedlands, Western Australia 6009, Australia.
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43
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Chinetti-Gbaguidi G, Staels B. PPARβ in macrophages and atherosclerosis. Biochimie 2016; 136:59-64. [PMID: 28011212 DOI: 10.1016/j.biochi.2016.12.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 12/09/2016] [Accepted: 12/10/2016] [Indexed: 12/19/2022]
Abstract
Macrophages are central cells in the genesis and development of atherosclerosis, one of the major causes of cardiovascular diseases. Macrophages take up lipids (mainly cholesterol and triglycerides) from lipoproteins thus transforming into foam cells. Moreover, through the efflux pathway, macrophages are the main actors of the elimination of excessive tissue cholesterol toward extra-cellular acceptors. Macrophages participate in the control of inflammation by displaying different functional phenotypes, from the M1 pro-inflammatory to the M2 anti-inflammatory state. The nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)β (also called PPARδ or PPARβ/δ) is expressed in macrophages where it plays a different role in the control of lipid metabolism, inflammation and phagocytosis of apoptotic cells. This review will summarize our current understanding of how PPARβ regulates macrophage biology and its impact on atherosclerosis. Differences between studies and species-specific macrophage gene regulation will be discussed.
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Affiliation(s)
| | - B Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, EGID, F-59000, Lille, France.
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44
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Smith RW, Coleman JD, Thompson JT, Vanden Heuvel JP. Therapeutic potential of GW501516 and the role of Peroxisome proliferator-activated receptor β/δ and B-cell lymphoma 6 in inflammatory signaling in human pancreatic cancer cells. Biochem Biophys Rep 2016; 8:395-402. [PMID: 28955982 PMCID: PMC5614479 DOI: 10.1016/j.bbrep.2016.10.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 09/07/2016] [Accepted: 10/27/2016] [Indexed: 01/09/2023] Open
Abstract
Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a member of the nuclear receptor superfamily and a ligand-activated transcription factor that is involved in the regulation of the inflammatory response via activation of anti-inflammatory target genes and ligand-induced disassociation with the transcriptional repressor B-cell lymphoma 6 (BCL6). Chronic pancreatitis is considered to be a significant etiological factor for pancreatic cancer development, and a better understanding of the underlying mechanisms of the transition between inflammation and carcinogenesis would help further elucidate chemopreventative options. The aim of this study was to determine the role of PPARβ/δ and BCL6 in human pancreatic cancer of ductal origin, as well as the therapeutic potential of PPARβ/δ agonist, GW501516. Over-expression of PPARβ/δ inhibited basal and TNFα-induced Nfkb luciferase activity. GW501516-activated PPARβ/δ suppressed TNFα-induced Nfkb reporter activity. RNAi knockdown of Pparb attenuated the GW501516 effect on Nfkb luciferase, while knockdown of Bcl6 enhanced TNFα-induced Nfkb activity. PPARβ/δ activation induced expression of several anti-inflammatory genes in a dose-dependent manner, and GW501516 inhibited Mcp1 promoter-driven luciferase in a BCL6-dependent manner. Several pro-inflammatory genes were suppressed in a BCL6-dependent manner. Conditioned media from GW501516-treated pancreatic cancer cells suppressed pro-inflammatory expression in THP-1 macrophages as well as reduced invasiveness across a basement membrane. These results demonstrate that PPARβ/δ and BCL6 regulate anti-inflammatory signaling in human pancreatic cancer cells by inhibiting NFκB and pro-inflammatory gene expression, and via induction of anti-inflammatory target genes. Activation of PPARβ/δ may be a useful target in pancreatic cancer therapeutics.
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Affiliation(s)
| | | | | | - John P. Vanden Heuvel
- Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA, United States
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Hwang JS, Ham SA, Yoo T, Lee WJ, Paek KS, Lee CH, Seo HG. Sirtuin 1 Mediates the Actions of Peroxisome Proliferator-Activated Receptor δ on the Oxidized Low-Density Lipoprotein-Triggered Migration and Proliferation of Vascular Smooth Muscle Cells. Mol Pharmacol 2016; 90:522-529. [PMID: 27573670 DOI: 10.1124/mol.116.104679] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 08/26/2016] [Indexed: 12/21/2022] Open
Abstract
Peroxisome proliferator-activated receptor δ (PPARδ) has been implicated in vascular pathophysiology. However, its functions in atherogenic changes of the vascular wall have not been fully elucidated. PPARδ activated by GW501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid) significantly inhibited the migration and proliferation of vascular smooth muscle cells (VSMCs) triggered by oxidized low-density lipoprotein (oxLDL). These GW501516-mediated effects were significantly reversed by PPARδ-targeting small-interfering RNA (siRNA), indicating that PPARδ is involved in the action of GW501516. The antiproliferative effect of GW501516 was directly linked to cell cycle arrest at the G0/G1 to S phase transition, which was followed by the down-regulation of cyclin-dependent kinase 4 along with increased levels of p21 and p53. In VSMCs treated with GW501516, the expression of sirtuin 1 (SIRT1) mRNA and protein was time-dependently increased. This GW501516-mediated up-regulation of SIRT1 expression was also demonstrated even in the presence of oxLDL. In addition, GW501516-dependent inhibition of oxLDL-triggered migration and proliferation of VSMCs was almost completely abolished in the presence of SIRT1-targeting siRNA. These effects of GW501516 on oxLDL-triggered phenotypic changes of VSMCs were also demonstrated via activation or inhibition of SIRT1 activity by resveratrol or sirtinol, respectively. Finally, gain or loss of SIRT1 function imitated the action of PPARδ on oxLDL-triggered migration and proliferation of VSMCs. Taken together, these observations indicate that PPARδ-dependent up-regulation of SIRT1 contributes to the antiatherogenic activities of PPARδ by suppressing the migration and proliferation of VSMCs linked to vascular diseases such as restenosis and atherosclerosis.
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Affiliation(s)
- Jung Seok Hwang
- College of Animal Bioscience and Technology, Konkuk University, Seoul (J.S.H., S.A.H., T.Y., W.J.L., C.-H.L., H.G.S.); Department of Nursing, Semyung University, Jecheon (K.S.P.), South Korea
| | - Sun Ah Ham
- College of Animal Bioscience and Technology, Konkuk University, Seoul (J.S.H., S.A.H., T.Y., W.J.L., C.-H.L., H.G.S.); Department of Nursing, Semyung University, Jecheon (K.S.P.), South Korea
| | - Taesik Yoo
- College of Animal Bioscience and Technology, Konkuk University, Seoul (J.S.H., S.A.H., T.Y., W.J.L., C.-H.L., H.G.S.); Department of Nursing, Semyung University, Jecheon (K.S.P.), South Korea
| | - Won Jin Lee
- College of Animal Bioscience and Technology, Konkuk University, Seoul (J.S.H., S.A.H., T.Y., W.J.L., C.-H.L., H.G.S.); Department of Nursing, Semyung University, Jecheon (K.S.P.), South Korea
| | - Kyung Shin Paek
- College of Animal Bioscience and Technology, Konkuk University, Seoul (J.S.H., S.A.H., T.Y., W.J.L., C.-H.L., H.G.S.); Department of Nursing, Semyung University, Jecheon (K.S.P.), South Korea
| | - Chi-Ho Lee
- College of Animal Bioscience and Technology, Konkuk University, Seoul (J.S.H., S.A.H., T.Y., W.J.L., C.-H.L., H.G.S.); Department of Nursing, Semyung University, Jecheon (K.S.P.), South Korea
| | - Han Geuk Seo
- College of Animal Bioscience and Technology, Konkuk University, Seoul (J.S.H., S.A.H., T.Y., W.J.L., C.-H.L., H.G.S.); Department of Nursing, Semyung University, Jecheon (K.S.P.), South Korea
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Elevated Adiponectin Levels Suppress Perivascular and Aortic Inflammation and Prevent AngII-induced Advanced Abdominal Aortic Aneurysms. Sci Rep 2016; 6:31414. [PMID: 27659201 PMCID: PMC5034224 DOI: 10.1038/srep31414] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 07/19/2016] [Indexed: 12/26/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) is a degenerative disease characterized by aortic dilation and rupture leading to sudden death. Currently, no non-surgical treatments are available and novel therapeutic targets are needed to prevent AAA. We investigated whether increasing plasma levels of adiponectin (APN), a pleiotropic adipokine, provides therapeutic benefit to prevent AngII-induced advanced AAA in a well-established preclinical model. In the AngII-infused hyperlipidemic low-density lipoprotein receptor-deficient mouse (LDLR-/-) model, we induced plasma APN levels using a recombinant adenovirus expressing mouse APN (AdAPN) and as control, adenovirus expressing green florescent protein (AdGFP). APN expression produced sustained and significant elevation of total and high-molecular weight APN levels and enhanced APN localization in the artery wall. AngII infusion for 8 weeks induced advanced AAA development in AdGFP mice. Remarkably, APN inhibited the AAA development in AdAPN mice by suppressing aortic inflammatory cell infiltration, medial degeneration and elastin fragmentation. APN inhibited the angiotensin type-1 receptor (AT1R), inflammatory cytokine and mast cell protease expression, and induced lysyl oxidase (LOX) in the aortic wall, improved systemic cytokine profile and attenuated adipose inflammation. These studies strongly support APN therapeutic actions through multiple mechanisms inhibiting AngII-induced AAA and increasing plasma APN levels as a strategy to prevent advanced AAA.
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Tan NS, Vázquez-Carrera M, Montagner A, Sng MK, Guillou H, Wahli W. Transcriptional control of physiological and pathological processes by the nuclear receptor PPARβ/δ. Prog Lipid Res 2016; 64:98-122. [PMID: 27665713 DOI: 10.1016/j.plipres.2016.09.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/31/2016] [Accepted: 09/20/2016] [Indexed: 12/14/2022]
Affiliation(s)
- Nguan Soon Tan
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Academia, 20 College Road, 169856, Singapore; Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Agency for Science Technology & Research, 138673, Singapore; KK Research Centre, KK Women's and Children's Hospital, 100 Bukit Timah Road, 229899, Singapore.
| | - Manuel Vázquez-Carrera
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Pediatric Research Institute-Hospital Sant Joan de Déu, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain
| | | | - Ming Keat Sng
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Academia, 20 College Road, 169856, Singapore
| | - Hervé Guillou
- INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex 3, France
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological University, Academia, 20 College Road, 169856, Singapore; INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex 3, France; Center for Integrative Genomics, University of Lausanne, Le Génopode, CH 1015 Lausanne, Switzerland.
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Vascular smooth muscle cell dysfunction in diabetes: nuclear receptors channel to relaxation. Clin Sci (Lond) 2016; 130:1837-9. [DOI: 10.1042/cs20160518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 08/08/2016] [Indexed: 11/17/2022]
Abstract
Endothelial dysfunction and impaired vascular relaxation represent a common cause of microvascular disease in patients with diabetes. Although multiple mechanisms underlying altered endothelial cell function in diabetes have been described, there is currently no specific and approved pharmacological treatment. In this edition of Clinical Science, Morales-Cano et al. characterize voltage-dependent K+ (Kv) channels as genes regulated by pharmacological activation of peroxisome proliferator-activated receptor-b/d (PPARb/d). Diabetes altered Kv channel function leading to impaired coronary artery relaxation, which was prevented by pharmacological activation of PPARb/d. These studies highlight an important mechanism of vascular dysfunction in diabetes and point to a potential approach for therapy, particularly considering that PPARb/d ligands have been developed and tested in small clinical trials.
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Choy KW, Mustafa MR, Lau YS, Liu J, Murugan D, Lau CW, Wang L, Zhao L, Huang Y. Paeonol protects against endoplasmic reticulum stress-induced endothelial dysfunction via AMPK/PPARδ signaling pathway. Biochem Pharmacol 2016; 116:51-62. [PMID: 27449753 DOI: 10.1016/j.bcp.2016.07.013] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 07/18/2016] [Indexed: 12/31/2022]
Abstract
Endoplasmic reticulum (ER) stress in endothelial cells often leads to endothelial dysfunction which underlies the pathogenesis of cardiovascular diseases. Paeonol, a major phenolic component extracted from Moutan Cortex, possesses various medicinal benefits which have been used extensively in traditional Chinese medicine. The present study investigated the protective mechanism of paeonol against tunicamycin-induced ER stress in isolated mouse aortas and human umbilical vein endothelial cells (HUVECs). Vascular reactivity in aorta was measured using a wire myograph. The effects of paeonol on protein expression of ER stress markers, reactive oxygen species (ROS) production, nitric oxide (NO) bioavailability and peroxisome proliferator-activated receptor δ (PPARδ) activity in the vascular wall were assessed by Western blot, dihydroethidium fluorescence (DHE) or lucigenin enhanced-chemiluminescence, 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA) and dual luciferase reporter assay, respectively. Ex vivo treatment with paeonol (0.1μM) for 16h reversed the impaired endothelium-dependent relaxations in C57BJ/6J and PPARδ wild type (WT) mouse aortas following incubation with tunicamycin (0.5μg/mL). Elevated ER stress markers, oxidative stress and reduction of NO bioavailability induced by tunicamycin in HUVECs, C57BJ/6J and PPARδ WT mouse aortas were reversed by paeonol treatment. These beneficial effects of paeonol were diminished in PPARδ knockout (KO) mouse aortas. Paeonol increased the expression of 5' adenosine monophosphate-activated protein kinase (AMPK) and PPARδ expression and activity while restoring the decreased phosphorylation of eNOS. The present study delineates that paeonol protects against tunicamycin-induced vascular endothelial dysfunction by inhibition of ER stress and oxidative stress, thus elevating NO bioavailability via the AMPK/PPARδ signaling pathway.
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Affiliation(s)
- Ker-Woon Choy
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Mohd Rais Mustafa
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
| | - Yeh Siang Lau
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jian Liu
- Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Dharmani Murugan
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Chi Wai Lau
- Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Li Wang
- Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Lei Zhao
- Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Yu Huang
- Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
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Romero M, Jiménez R, Toral M, León-Gómez E, Gómez-Gúzman M, Sánchez M, Zarzuelo MJ, Rodríguez-Gómez I, Rath G, Tamargo J, Pérez-Vizcaíno F, Dessy C, Duarte J. Vascular and Central Activation of Peroxisome Proliferator-Activated Receptor-β Attenuates Angiotensin II-Induced Hypertension: Role of RGS-5. J Pharmacol Exp Ther 2016; 358:151-63. [PMID: 27189971 DOI: 10.1124/jpet.116.233106] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 04/25/2016] [Indexed: 11/22/2022] Open
Abstract
Activation of peroxisome proliferator-activated receptor-β/δ (PPARβ) lowers blood pressure in genetic and mineralocorticoid-induced hypertension. Regulator of G-protein-coupled receptor signaling 5 (RGS5) protein, which interferes in angiotensin II (AngII) signaling, is a target gene to PPARβ The aim of the present study was to examine whether PPARβ activation in resistance arteries and brain tissues prevents the elevated blood pressure in AngII-induced hypertension and evaluate the role of RGS5 in this effect. C57BL/6J male mice were divided into five groups (control mice, PPARβ agonist [4-[[[2-[3-Fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid (GW0742)-treated mice AngII-infused mice, GW0742-treated AngII-infused mice, and AngII-infused mice treated with GW0742 plus PPARβ antagonist 3-[[[2-Methoxy-4-(phenylamino)phenyl]amino]sulfonyl]-2-thiophenecarboxylic acid methyl ester (GSK0660)) and were followed for 3 weeks. GW0742 prevented the increase in both arterial blood pressure and plasma noradrenaline levels and the higher reduction of blood pressure after ganglionic blockade, whereas it reduced the mesenteric arterial remodeling and the hyper-responsiveness to vasoconstrictors (AngII and endothelin-1) in AngII-infused mice. These effects were accompanied by an inhibition of NADPH oxidase expression and activity in the brain. Gene expression profiling revealed a marked loss of brainstem and vascular RGS5 in AngII-infused mice, which was restored by GW0742. GW0742-induced effects were abolished by GSK0660. Small interfering RNA targeting RGS5 caused augmented contractile response to AngII in resistance mesenteric arteries and blunted the inhibitory effect of GW0742 on this response. In conclusion, GW0742 exerted antihypertensive effects, restoring sympathetic tone and vascular structure and function in AngII-infused mice by PPARβ activation in brain and vessels inhibiting AngII signaling as a result of RGS5 upregulation.
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Affiliation(s)
- Miguel Romero
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Rosario Jiménez
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Marta Toral
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Elvira León-Gómez
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Manuel Gómez-Gúzman
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Manuel Sánchez
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - María José Zarzuelo
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Isabel Rodríguez-Gómez
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Geraldine Rath
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Juan Tamargo
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Francisco Pérez-Vizcaíno
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Chantal Dessy
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
| | - Juan Duarte
- Department of Pharmacology, School of Pharmacy (M.R., R.J., M.T., M.G.-G., M.S., M.J.Z., J.D.), and Department of Physiology (I.R.-G.); University of Granada, Granada, Spain; Center for Biomedical Research, Granada, Spain (R.J., J.D.); Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, School of Medicine, University of Louvain, Brussels, Belgium (E.L.-G., G.R., C.D.); Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain (J.T., F.P.-V.); and Ciber Enfermedades Respiratorias (Ciberes) and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain (F.P.-V.)
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