Subcellular microRNAs in diabetic cardiomyopathy

Abstract

Cardiovascular complications are the leading causes of diabetes-related morbidity and mortality. The high incidence and poor prognosis of heart failure in diabetic patients have been associated, in part, to the presence of an underlying cardiomyopathy characterized by cardiac hypertrophy, cardiomyocytes apoptosis, and fibrosis. It has been unclear about the mechanism that connects diabetes mellitus to the development of cardiovascular dysfunction. Micro(mi)RNAs represent a class of small, 18- to 28-nucleotide-long, non-coding RNA molecules. MiRNAs typically suppress gene expression at the post-transcriptional levels by binding directly to the 3'-UTR of the target mRNAs in the cytoplasm. Interestingly, recent studies suggest that miRNAs may also regulate gene expression in a positive manner. Our recent studies have shown that subcellular miRNAs, such as cytosol-, mitochondria- and nucleus-localized miRNAs, were dramatically dysregulated in diabetic cardiomyopathy. Specifically, cytoplasm localized miRNAs regulate genes expression in a post-transcriptional manner. Nuclear localized miRNAs regulate gene transcription or chromosomal reconstruction through the non-canonical mechanism. Mitochondrial miRNAs stimulate, rather than repress, the translation of specific mitochondrial genome-encoded transcripts. By reviewing these latest discovered functions of subcellular miRNAs in diabetic animal models, we identified new mechanistic insights for diabetic cardiomyopathy. Understanding the nature of subcellular miRNAs will provide new therapeutic targets against diabetes-associated cardiac complications in the near future.

Keywords: Subcellular miRNAs; diabetic cardiomyopathy; transcription; translation.

Figure 1

Nuclear miR-320 mediates diabetes-induced cardiac dysfunction by activating the transcription of the fatty acid metabolic gene CD36 to cause lipotoxicity in the heart. MiR-320, MicroRNA-320; FFA, free fatty acids; TG, triacylglycerol; CD36, cluster of differentiation 36; Ago2, Argonaute RISC Catalytic Component 2; Pol II, RNA polymerase II.