Abstract
To identify circulating microRNAs that are differentially expressed in severe coronary heart disease with well or poorly developed collateral arteries and to investigate their mechanisms of action in vivo and in vitro. In our study, we identified a circulating microRNA, miR-15b-5p, with low expression that, nevertheless, characterized patients with sufficient coronary collateral artery function. Moreover, in murine hindlimb ischemia model, in situ hybridization identified that miR-15b-5p was specifically expressed in vascular endothelial cells of adductors in sham group and was remarkably downregulated after femoral artery ligation. Overexpressed miR-15b-5p significantly inhibited arteriogenesis and angiogenesis in mice. In vitro, both under basal and vascular endothelial growth factor stimulation, loss-of-function or gain-of-function studies suggested that miR-15b-5p significantly promoted or depressed the migration and proliferation of endothelial cells. We identified AKT3 (protein kinase B-3) as a direct target of miR-15b-5p. Interestingly, AKT3 deficiency by injection with Chol-AKT3-siRNA obviously suppressed arteriogenesis and the recovery of blood perfusion after femoral ligation in mice. These results indicate that circulating miR-15b-5p is a suitable biomarker for discriminating between patients with well-developed or poorly developed collaterals. Moreover, miR-15b-5p is a key regulator of arteriogenesis and angiogenesis, which may represent a potential therapeutic target for ischemic disease.
Highlights
Arteriogenesis, the basic process of coronary collateral formation, during which preexisting small arterioles are remodeled into large collateral arteries to divert blood flow around stenotic lesions, happens upstream of the ischemic area and is triggered by increasing fluid shear stress, rather than ischemia
Shear stress sensed by endothelial cells (ECs) triggers an inflammatory response that leads to a complex set of events involving interactions among various cell types and signaling circuits.[1]
Circulating miR-15b-5p Correlates With Insufficient Coronary Collateral Artery Function in the Patients of Coronary Artery Disease Based on the Rentrop scoring system, all patients in a highly selected criterion with triple vessel disease or left main coronary artery disease were divided into 2 groups: poor coronary collateral circulation (CCC; grades 0 and 1) and good CCC
Summary
MiR-15b-5p Inhibits Arteriogenesis and Angiogenesis in Mice After Hindlimb Ischemia To determine the role of miR-15b-5p in collateral growth in vivo, gain-of-function studies by locally injecting with agomiR-15b into adductors after ischemia surgery were performed.
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