Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart

被引:75
作者
Rawal, Shruti [1 ]
Munasinghe, Pujika Emani [1 ]
Nagesh, Prashanth Thevkar [2 ]
Lew, Jason Kar Sheng [1 ]
Jones, Gregory T. [3 ]
Williams, Michael J. A. [4 ]
Davis, Philip [5 ]
Bunton, Dick [5 ]
Galvin, Ivor F. [5 ]
Manning, Patrick [4 ]
Lamberts, Regis R. [1 ]
Katare, Rajesh [1 ]
机构
[1] Univ Otago, Dept Physiol, HeartOtago, Dunedin, New Zealand
[2] Univ Otago, Dunedin Sch Med, Dept Microbiol & Immunol, Dunedin, New Zealand
[3] Univ Otago, Dunedin Sch Med, Dept Surg, Dunedin, New Zealand
[4] Univ Otago, Dunedin Sch Med, Dept Med, Dunedin, New Zealand
[5] Univ Otago, Dunedin Sch Med, Dept Cardiothorac Surg, Dunedin, New Zealand
关键词
CARDIAC FIBROSIS; MOLECULAR-MECHANISMS; EJECTION FRACTION; CELL; CARDIOMYOPATHY; FIBROBLAST; GENE; MYOCARDIUM; MICRORNAS; DISEASE;
D O I
10.1042/CS20160916
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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-a receptor-1 (TGFaR1) 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 TGFaR1 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.
引用
收藏
页码:847 / 863
页数:17
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