MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr-/- mice

Abstract

Background and Objective The miR-143/145 cluster regulates VSMC specific gene expression, thus controlling differentiation, plasticity and contractile function, and promoting the VSMC phenotypic switch from a contractile/non-proliferative to a migrating/proliferative state. More recently increased miR-145 expression was observed in human carotid atherosclerotic plaques from symptomatic patients. The goal of this study was to investigate the contribution of miR-143/145 during atherogenesis by generating mice lacking miR-143/145 on an Ldlr-deficient background. Methods and Results Ldlr−/− and Ldlr−/−-miR-143/145−/− (DKO) were fed a Western diet (WD) for 16 weeks. At the end of the treatment, the lipid profile and the atherosclerotic lesions were assessed in both groups of mice. Absence of miR-143/145 significantly reduced atherosclerotic plaque size and macrophage infiltration. Plasma total cholesterol levels were lower in DKO and FLPC analysis showed decreased cholesterol content in VLDL and LDL fractions. Interestingly miR-143/145 deficiency per se resulted in increased hepatic and vascular ABCA1 expression. Experiments with the luciferase coding sequence fused to the ABCA1 3’UTR, Western blotting, qRT-PCR and mimicMiR confirmed the direct regulation of ABCA1 expression by miR-145. Conclusions miR-143/145 deficiency significantly reduces atherosclerosis in mice. Therapeutic inhibition of miR-145 might be useful for treating atherosclerotic vascular disease.

MicroRNA-mediated mechanisms of the cellular stress response in atherosclerosis

“…132 Despite the atheroprotective role of miR-145 in SMCs, genetic deletion of the miR-143/145 cluster reduces plasma cholesterol levels and atherosclerosis by targeting the ABC transporter A family member 1 (ABCA1) in hepatocytes. 133 Moreover, SMCs induce the expression of a subset of anti-inflammatory miRNAs in endothelial cells, such as miR-98, miR-146a, miR-451, and miR-708, through paracrine signalling that activates the NF-κB pathway. 134 SMC-induced expression of miR-146a in endothelial cells is further amplified by β 1 and β 3 i ntegrin-dependent binding of NRF2 to the promoter region of miR-146a.…”

Noncoding RNAs in diabetes vascular complications

“…In line, the transduction of miR-145 into a rabbit vein used for bypass grafting prevented vein graft disease by regulation of VSMC phenotype [47]. On the other side, miR-143/ 145 deficiency was reported to attenuate the progression of plaque formation in a mouse model of atherosclerosis [48], indicating that more research is necessary to clarify the role on this miRNA cluster in vascular disease.…”

miRNA‑145 is associated with spontaneous hypertension by targeting SLC7A1

“…The role of miR-145 in hypertension has also been reported; Santovito et al (27) examined the expression of miR-145 in the atherosclerotic plaques of patients with and without essential hypertension, and identified that miR-145 was overexpressed in patients with hypertension. Sala et al (14) investigated a miR-143/miR-145 knockout mouse model and observed that these mice had thinner arteries with reduced vascular tone and smooth muscle layer width, which led to a significantly lower blood pressure. These results suggest that miR-143 and miR-145 serve key roles in regulating VSMC function and blood pressure.…”

“…It has also been observed that miR-145 was aberrantly expressed in the serum of patients with coronary artery disease (10) and acute myocardial infarction (11), suggesting that miR-145 is a potential biomarker for the diagnosis of cardiovascular diseases. Furthermore, several studies have indicated that the abnormal expression of miR-145 may be associated with the pathogenesis of cardiovascular diseases, including pulmonary arterial hypertension (12), myocardial infarction (13) and atherosclerosis (14). The association between miR-145 and hypertension has also been discussed previously (15); however, further investigation is required to determine the underlying molecular mechanisms of this association.…”