MicroRNA-25 Protects Smooth Muscle Cells against Corticosterone-Induced Apoptosis

Abstract

Background and Aims. Vascular smooth muscle cells (VSMCs) are central components of atherosclerotic plaque. Loss of VSMCs through apoptotic cell death can cause fibrous cap thinning, necrotic core formation, and calcification that may destabilize plaque. Elevated glucocorticoid levels caused by psychological stress promote VSMC apoptosis and can exacerbate atherosclerosis in mice and humans. Changes in the levels of antiapoptosis microRNA-25 (miR-25) have been linked with heart disease, inflammation, VSMC phenotype, oxidative stress, and apoptosis. Here, we investigated the pathways and mechanisms of glucocorticoid-induced apoptosis of mouse VSMCs and the protective role of miR-25. Methods. Primary mouse VSMCs were cultured +/- corticosterone for 48 h. Apoptosis, ROS, apoptotic protein activities, miR-25, MOAP1, a miR-25 target, and p70S6 kinase were quantified at intervals. The roles of miR-25 were assessed by treating cells with lenti-pre-miR-25 and anti-miR-25. Results. VSMC apoptosis, caspase-3 activity, and Bax were increased by corticosterone, and cell death was paralleled by marked loss of miR-25. Protection was conferred by pre-miR-25 and exacerbated by anti-miR-25. Pre-miR-25 conferred reduced expression of the proapoptotic protein MOAP1, and the protective effects of pre-miR-25 were abrogated by overexpressing MOAP1. The antiapoptotic effects of miR-25 were paralleled by inhibition of the p70S6K pathway, a convergence target for the survival signaling pathways, and protection by pre-miR-25 was abrogated by the p70S6k inhibitor rapamycin. Conclusions. MicroRNA-25 blocks corticosterone-induced VSMC apoptosis by targeting MOAP1 and the p70S6k pathway. Therapeutic manipulation of miR-25 may reduce atherosclerosis and unstable plaque formation associated with chronic stress.

MiR-126-HMGB1-HIF-1 Axis Regulates Endothelial Cell Inflammation during Exposure to Hypoxia-Acidosis

“…Measurement of ROS. ROS were measured using an Oxi-Select ROS assay kit, exactly as described by the manufacturer and as previously reported [64].…”

Apoptosis in the Extraosseous Calcification Process

“…Furthermore, miR-25 can inhibit corticosterone-induced VSMC apoptosis by targeting the pro-apoptotic protein MOAP1 and possibly also the p70S6k pathway [ 305 ]. MOAP1 promotes caspase-dependent apoptosis by binding pro-apoptotic BAX via its Bcl-2 homology-3- (BH3-) like domain, and it is up-regulated upon several apoptotic stimuli [ 306 ].…”

“…MOAP1 promotes caspase-dependent apoptosis by binding pro-apoptotic BAX via its Bcl-2 homology-3- (BH3-) like domain, and it is up-regulated upon several apoptotic stimuli [ 306 ]. Since MOAP is a direct target for miR-25, it has been suggested that miR-25-dependent down-regulation of MOAP1 may represent a key mechanism in apoptosis inhibition with positive effects on atherogenesis and eventually on calcification [ 305 ]. It has to be further investigated if these data may also be relevant for therapeutic implications in humans.…”

The Epigenetic Landscape of Vascular Calcification: An Integrative Perspective

“…MiR-25, also an onco-miR, was reported to interfere with calcium handling, attenuate inflammation, and decreased apoptosis in myocardial and renal tissues [87]. Zhang and colleagues showed that in mouse VSMCs, over-expression of miR-25 could ameliorate exogenous stimuli-triggered apoptosis and potentially subsequent calcification [51]. MiR-26a plays a pivotal role in different types of cancers by regulating cellular proliferation and participates in cardiovascular pathophysiology by targeting glycogen synthase kinase (GSK)-3β, a Wnt/β-catenin pathway component [88].…”