Shruti Rawal1, Pujika Emani Munasinghe1, Prashanth Thevkar Nagesh2, Jason Kar Sheng Lew1, Gregory T Jones3, Michael J A Williams4, Philip Davis5, Dick Bunton5, Ivor F Galvin5, Patrick Manning4, Regis R Lamberts1, Rajesh Katare6. 1. Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand. 2. Department of Microbiology and Immunology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. 3. Department of Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. 4. Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. 5. Department of Cardiothoracic Surgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. 6. Department of Physiology, HeartOtago, University of Otago, Dunedin, New Zealand rajesh.katare@otago.ac.nz.
Abstract
Aim: Myocardial fibrosis is a well-established cause of increased myocardial stiffness and subsequent diastolic dysfunction in the diabetic heart. The molecular regulators that drive the process of fibrotic events in the diabetic heart are still unknown. We determined the role of the microRNA (miR)-15 family in fibrotic remodelling of the diabetic heart.Methods and results: Right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic (ND) patients undergoing coronary artery bypass graft surgery showed significant down-regulation of miR-15a and -15b. This was associated with marked up-regulation of pro-fibrotic transforming growth factor-β receptor-1 (TGFβR1) and connective tissue growth factor (CTGF), direct targets for miR-15a/b and pro-senescence p53 protein. Interestingly, down-regulation of miR-15a/b preceded the development of diastolic dysfunction and fibrosis in Type 2 diabetic mouse heart. Therapeutic restoration of miR-15a and -15b in HL-1 cardiomyocytes reduced the activation of pro-fibrotic TGFβR1 and CTGF, and the pro-senescence p53 protein expression, confirming a causal regulation of these fibrotic and senescence mediators by miR-15a/b. Moreover, conditioned medium (CM) collected from cardiomyocytes treated with miR-15a/b markedly diminished the differentiation of diabetic human cardiac fibroblasts. Conclusion: Our results provide first evidence that early down-regulation of miR-15a/b activates fibrotic signalling in diabetic heart, and hence could be a potential target for the treatment/prevention of diabetes-induced fibrotic remodelling of the heart.
Aim: Myocardial fibrosis is a well-established cause of increased myocardial stiffness and subsequent diastolic dysfunction in the diabetic heart. The molecular regulators that drive the process of fibrotic events in the diabetic heart are still unknown. We determined the role of the microRNA (miR)-15 family in fibrotic remodelling of the diabetic heart.Methods and results: Right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic (ND) patients undergoing coronary artery bypass graft surgery showed significant down-regulation of miR-15a and -15b. This was associated with marked up-regulation of pro-fibrotic transforming growth factor-β receptor-1 (TGFβR1) and connective tissue growth factor (CTGF), direct targets for miR-15a/b and pro-senescence p53 protein. Interestingly, down-regulation of miR-15a/b preceded the development of diastolic dysfunction and fibrosis in Type 2 diabeticmouse heart. Therapeutic restoration of miR-15a and -15b in HL-1 cardiomyocytes reduced the activation of pro-fibrotic TGFβR1 and CTGF, and the pro-senescence p53 protein expression, confirming a causal regulation of these fibrotic and senescence mediators by miR-15a/b. Moreover, conditioned medium (CM) collected from cardiomyocytes treated with miR-15a/b markedly diminished the differentiation of diabetichuman cardiac fibroblasts. Conclusion: Our results provide first evidence that early down-regulation of miR-15a/b activates fibrotic signalling in diabetic heart, and hence could be a potential target for the treatment/prevention of diabetes-induced fibrotic remodelling of the heart.
Authors: Joseph U Igietseme; Yusuf Omosun; Tamas Nagy; Olga Stuchlik; Matthew S Reed; Qing He; James Partin; Kahaliah Joseph; Debra Ellerson; Zenas George; Jason Goldstein; Francis O Eko; Claudiu Bandea; Jan Pohl; Carolyn M Black Journal: Infect Immun Date: 2017-12-19 Impact factor: 3.441