T-Cell Mineralocorticoid Receptor Deficiency Attenuates Pathologic Ventricular Remodelling After Myocardial Infarction |
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| Affiliation: | 1. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;2. National Center for Stomatology, National Clinical Research Center for Oral Diseases and Shanghai Key Laboratory of Stomatology, Shanghai, China;3. Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People''s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China;1. Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada;2. Department of Medicine, Queen’s University, Kingston, Ontario, Canada;3. Division of Cardiology, University of Toronto, Toronto, Ontario, Canada;4. MERIT and Department of Medicine, McMaster University, Hamilton, Ontario, Canada;5. St. Joseph’s Health Care London, Western University, London, Ontario, Canada;1. Women’s College Research Institute, Women’s College Hospital, Toronto, Ontario, Canada;2. ICES, Toronto, Ontario, Canada;3. Cardiovascular Division, Department of Medicine, Women’s College Hospital, Toronto, Ontario, Canada;4. Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada;5. Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada;6. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada;7. Schulich Heart Centre, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada;8. Department of Family Medicine, Women’s College Hospital, Toronto, Ontario, Canada;1. Department of Medicine, Division of Cardiology, Queen’s University, Kingston, Ontario, Canada;2. Division of Cardiology, Department of Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada;3. Division of Cardiology, the University of Toronto, University Health Network, Toronto, Ontario, Canada;4. Department of Internal Medicine, Section of Cardiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada;5. Montreal Heart Institute, University of Montreal, Montreal, Québec, Canada;6. Division of Cardiology, Dalhousie University, Halifax, Nova Scotia, Canada;7. Division of Cardiology, Department of Medicine, Western University, London Health Sciences Centre, London, Ontario, Canada;8. University of Toronto, Toronto, Ontario, Canada;9. Schulich School of Business-York University, Toronto, Ontario, Canada;10. Echocardiography laboratory, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada;11. Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Québec, Canada;1. Department of Medicine, Centre Hospitalier de l’Universite de Montréal, Montréal, Québec, Canada;2. Population Health Research Institute, Hamilton, Ontario, Canada;3. Department of Medicine, McMaster University, Hamilton, Ontario, Canada;4. Translational Medicine and Therapeutics William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;5. The Chinese University of Hong Kong, Hong Kong, China;6. Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada;7. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada;8. Department of Medicine, Western University, London, Ontario, Canada;9. Department of Outcome Research, Cleveland Clinic, Cleveland, Ohio, United States;10. Department of Cardiology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom;11. Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada;12. Anaesthesiology Department, Clinica Santa Maria, Santiago. Universidad de los Andes, Santiago, Chile;13. Department of Cardiology, University Hospital Basel, Basel, Switzerland;14. Center for Intensive Care and Perioperative Medicine, Jagiellonian University Medical College, Krakow, Poland;15. Department of Anaesthesia, University of KwaZulu-Natal, Durban, South Africa;p. Department of Anaesthesiology and Pain Medicine, University of Ottawa, Ottawa, Ontario, Canada;1. Department of Cardiology, Blacktown Hospital, Blacktown, New South Wales, Australia;2. School of Public Health and Community Medicine, University of New South Wales, Sydney, New South Wales, Australia;3. School of Medicine, Western Sydney University, Sydney, New South Wales, Australia;4. Department of Cardiology, Westmead Hospital, Westmead, New South Wales, Australia |
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| Abstract: | BackgroundMineralocorticoid receptor (MR) antagonists have been widely used to treat heart failure (HF). Studies have shown that MR in T cells plays important roles in hypertension and myocardial hypertrophy. However, the function of T-cell MR in myocardial infarction (MI) has not been elucidated.MethodsIn this study, we used T-cell MR knockout (TMRKO) mouse to investigate the effects of T-cell MR deficiency on MI and to explore the underlying mechanisms. Echocardiography and tissue staining were used to assess cardiac function, fibrosis, and myocardial apoptosis after MI. Flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect immune cell infiltration and inflammation.ResultsT-cell MR deficiency significantly improved cardiac function, promoted myocardial repair, and inhibited myocardial apoptosis, fibrosis, and inflammation after MI. Luminex assays revealed that TMRKO mice had significantly lower levels of interferon-gamma (IFN-γ) and interleukin-6 (IL-6) in serum and infarcted myocardium than littermate control mice. In cultured splenic T cells, MR deficiency suppressed IL-6 expression, whereas MR overexpression enhanced IL-6 expression. Chromatin immunoprecipitation (ChIP) assay demonstrated that MR bound to the MR response element on the promoter of IL-6 gene. Finally, T-cell MR deficiency significantly suppressed accumulation of macrophages in infarcted myocardium and differentiation of proinflammatory macrophages, thereby alleviating the consequences of MI.ConclusionsT-cell MR deficiency improved pathologic ventricular remodelling after MI, likely through inhibition of accumulation and differentiation of proinflammatory macrophages. At the molecular level, MR may work through IFN-γ and IL-6 in T cells to exert functions in MI. |
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