oa MicroRNA-34a regulates diabetes-induced impaired angiogenesis: Role of SIRT1

Background: Diabetes, characterized by chronic elevation of blood glucose levels, is associated with impaired angiogenesis, vascular dysfunction and a higher risk of cardiovascular diseases (CVD). Recently, a novel class of small non-coding RNAs (miRNAs, single-stranded RNA molecules comprising 21-23 nucleotides in length) has been identified as important transcriptional/posttranscriptional regulators of gene expression and plays a critical role in the control of most biological processes, including cell differentiation and proliferation, migration, development, and apoptosis. In most cases, miRNAs function as translational repressors and/or activators that exert their action by partially pairing to one or more sequences in the 3'- un-translational regions (3'-UTRs) of target mRNA. Sirtuin-1 (SIRT1), NAD+-dependent deacetylase, has emerged as an important therapeutic target as it regulates various genes involved in endothelial differentiation, proliferation and angiogenesis. In-silico analysis supports the hypothesis that SIRT1 is a potential target of endothelial specific miRNAs. miR-34a has been recently found to target SIRT1 and reported to be critically involved in angiogenesis. In this study, we have investigated whether miR-34a regulates diabetes-induced impaired angiogenesis by targeting SIRT1 in mouse microvascular endothelial cells (MMECs). Results: Real-time PCR analysis reveals that exposure of MMECs to high glucose (HG) results in a significant increase in miR-34a expression and this induction paralleled and correlated with altered expression of SIRT1, eNOS (phospho/acetylation), makers of angiogenesis (VEGF, Ang-1, Ang-2, TSP-1) as well as a significant impairment of tube-forming activity. Interestingly, inhibition of miR-34a increased SIRT1 expression and attenuated changes in downstream signaling and impaired angiogenesis in HG-exposed MMECs. Conclusion: miR-34a, via the regulation of SIRT1 expression, has an anti-angiogenic action in microvascular endothelial cells. Thus, miR-34a may represent a new therapeutic target for the prevention/treatment of diabetic vascular disease and provide a potential miRNA-based mechanism for the regulation of angiogenesis. The project is supported by UREP 13-116-3-024