Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice.

Abstract

AIMS/HYPOTHESIS:

MicroRNAs (miRs) have been suggested as potential therapeutic targets for heart diseases. Inhibition of miR-195 prevents apoptosis in cardiomyocytes stimulated with palmitate and transgenic overexpression of miR-195 induces cardiac hypertrophy and heart failure. We investigated whether silencing of miR-195 reduces diabetic cardiomyopathy in a mouse model of streptozotocin (STZ)-induced type 1 diabetes.

METHODS:

Type 1 diabetes was induced in C57BL/6 mice (male, 2 months old) by injections of STZ.

RESULTS:

MiR-195 expression was increased and levels of its target proteins (B cell leukaemia/lymphoma 2 and sirtuin 1) were decreased in STZ-induced type 1 and db/db type 2 diabetic mouse hearts. Systemically delivering an anti-miR-195 construct knocked down miR-195 expression in the heart, reduced caspase-3 activity, decreased oxidative stress, attenuated myocardial hypertrophy and improved myocardial function in STZ-induced mice with a concurrent upregulation of B cell leukaemia/lymphoma 2 and sirtuin 1. Diabetes reduced myocardial capillary density and decreased maximal coronary blood flow in mice. Knockdown of miR-195 increased myocardial capillary density and improved maximal coronary blood flow in diabetic mice. Upregulation of miR-195 sufficiently induced apoptosis in cardiomyocytes and attenuated the angiogenesis of cardiac endothelial cells in vitro. Furthermore, inhibition of miR-195 prevented apoptosis in cardiac endothelial cells in response to NEFA, an important feature of diabetes.

CONCLUSIONS/INTERPRETATION:

Therapeutic silencing of miR-195 reduces myocardial hypertrophy and improves coronary blood flow and myocardial function in diabetes, at least in part by reducing oxidative damage, inhibiting apoptosis and promoting angiogenesis. Thus, miR-195 may represent an alternative therapeutic target for diabetic heart diseases.

• Authors: Dong Zheng, Jian Ma, Yong Yu, Minghui Li, Rui Ni, Grace Wang, Ruizhen Chen, Jianmin Li, Guo-Chang Fan, James C Lacefield, Tianqing Peng
• Journal: Diabetologia (Diabetologia) Vol. 58 Issue 8 Pg. 1949-58 (Aug 2015) ISSN: 1432-0428 [Electronic] Germany
• PMID: 25994075 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN195a microRNA, mouse
• MicroRNAs
• Proto-Oncogene Proteins c-bcl-2
• Bcl2 protein, mouse
• Caspase 3
• Sirtuin 1

Topics

• Animals
• Caspase 3 (metabolism)
• Diabetes Mellitus, Experimental (genetics, metabolism)
• Diabetic Cardiomyopathies (genetics, metabolism)
• Gene Silencing
• Male
• Mice
• Mice, Inbred C57BL
• MicroRNAs (genetics, metabolism)
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism)
• Oxidative Stress (genetics)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Sirtuin 1 (genetics, metabolism)