Micro-RNA 92a as a Therapeutic Target for Cardiac Microvascular Dysfunction in Diabetes

Abstract

Microvascular dysfunction is a pathological hallmark of diabetes, and is central to the ethology of diabetes-associated cardiac events. Herein, previous studies have highlighted the role of the vasoactive micro-RNA 92a (miR-92a) in small, as well as large, animal models. In this study, we explore the effects of miR-92a on mouse and human cardiac microvascular endothelial cells (MCMEC, HCMEC), and its underlying molecular mechanisms. Diabetic HCMEC displayed impaired angiogenesis and a pronounced inflammatory phenotype. Quantitative PCR (qPCR) showed an upregulation of miR-92a in primary diabetic HCMEC. Downregulation of miR-92a by antagomir transfection in diabetic HCMEC rescued angiogenesis and ameliorated diabetic endothelial bed inflammation. Furthermore, additional analysis of potential in silico-identified miR-92a targets in diabetic HCMEC revealed the miR-92a dependent downregulation of an essential metalloprotease, ADAM10. Accordingly, downregulation of ADAM10 impaired angiogenesis and wound healing in MCMEC. In myocardial tissue slices from diabetic pigs, ADAM10 dysregulation in micro- and macro-vasculature could be shown. Altogether, our data demonstrate the role of miR-92a in cardiac microvascular dysfunction and inflammation in diabetes. Moreover, we describe for the first time the metalloprotease ADAM10 as a novel miR-92a target, mediating its anti-angiogenic effect.

Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options

“…In addition to the modifications to chromatin, several non-coding RNAs (miRNAs) are implicated in microvascular dysfunction through the targeting of relevant pathways involved in endothelial cell and VSMC damage in diabetes [ 132 ]. A direct link between hyperglycemia and upregulation of miR-92a, associated with inflammatory phenotype and impaired angiogenesis, has been demonstrated in cardiac microvascular ECs from human T2DM patients and in non-diabetic ECs cultured with higher glucose levels [ 133 ]. A very recent study on mouse cardiac microvascular ECs identified a novel molecular mechanism associated with the upregulation of miR-27a-3p.…”

Tailoring Treatment in Cardiovascular Diseases: The Role of Targeted Therapies

“…Similar findings were demonstrated in a large animal model of pigs where this miRNA could protect against ischemia/reperfusion injury [ 77 ]. Furthermore, research has shown that targeting miRNA-92A could serve as a suitable therapeutic approach for addressing diabetes-associated cardiac microvascular dysfunction [ 78 ].…”

Role and mechanism of miRNA in cardiac microvascular endothelial cells in cardiovascular diseases

“…MiRNA-92a can inhibit the expression of A disintegrin and metalloproteinase 10 (ADAM10), Krüpple-like factor2 (KLF2) and Krüpple-like factor4 (KLF4). ADAM10 promotes cell migration, KLF2 and KLF4 are important transcriptional regulators of anti-inflammatory and antioxidant activity ( 114 ). Therefore, cells in the high glucose group with elevated miRNA-92a expression have a significantly reduced ability to migrate and proliferate, and an increased inflammatory response.…”