Therapeutic knockdown of miR-320 improves deteriorated cardiac function in a pre-clinical model of non-ischemic diabetic heart disease

Abstract

Non-ischemic diabetic heart disease (NiDHD) is characterized by diastolic dysfunction and decreased or preserved systolic function, eventually resulting in heart failure. Accelerated apoptotic cell death because of alteration of molecular signaling pathways due to dysregulation in microRNAs (miRNAs) plays a significant role in the development of NiDHD. Here, we aimed to determine the pathological role of cardiomyocyte-enriched pro-apoptotic miR-320 in the development of NiDHD. We identified a marked upregulation of miR-320 that was associated with downregulation of its target protein insulin growth factor-1 (IGF-1) in human right atrial appendage tissue in the late stages of cardiomyopathy in type 2 diabetic db/db mice and high-glucose-cultured human ventricular cardiomyocytes (AC-16 cells). In vitro knockdown of miR-320 in high-glucose-exposed AC-16 cells using locked nucleic acid (LNA) anti-miR-320 markedly reduced high-glucose-induced apoptosis by restoring IGF-1 and Bcl-2. Finally, in vivo knockdown of miR-320 in 24-week-old type 2 diabetic db/db mice reduced cardiomyocyte apoptosis and interstitial fibrosis while restoring vascular density. This resulted in partial recovery of the impaired diastolic and systolic function. Our study provides evidence that miR-320 is a late-responding miRNA that aggravates apoptosis and cardiac dysfunction in the diabetic heart, and that therapeutic knockdown of miR-320 is beneficial in partially restoring the deteriorated cardiac function.