Microrna 143–145 Deficiency Impairs Vascular Function

Abstract

MicroRNAs are required for vascular smooth muscle growth, differentiation and function. MiR143-145 modulates cytoskeletal dynamics and acquisition of the contractile phenotype by smooth muscle cells. Lack of this miRNA cluster results in decreased blood pressure and reduced vasocontraction. As all these observations point to a key role for miR143-145 in the vasculature, we investigated whether miR143-145 deficiency is associated with impaired vascular tone. Vasocontraction was assessed in isolated aortic rings from miR143-145 KO and wild type animals incubated with increasing concentrations of phenylephrine (lO-9M to 10-s M) or KCI O.3M. In both cases, aortic vessel contraction was dramatically reduced in miR143-145 KO animals compared to controls. Next, aortic rings were pre-contracted with phenylephrine (EC60: 10-7M) and concentration responses for acetylcholine were obtained. A significantly reduced vasodilation was observed in miR143-145 KO animals compared to controls and similar results were obtained when an exogenous donor of nitric oxide (sodium nitroprusside) was used. Endothelial nitric oxide synthase or guanylate cyclase mRNA expression were not different between the animal groups thus suggesting to investigate the effect of other vasodilators. Isoprenaline mediated vasodilation was significantly reduced in miR143-145 KO animals compared to controls in the absence or in the presence of the guanylate cyclase inhibitor ODQ (10 4M), suggesting that also beta adrenergic vasodilation is impaired following miR143-145 deficiency. Finally, the effect of a stable mimetic prostacyclin, namely iloprost, was investigated and again a reduced vasodilation was observed in miR143-145 KO animals. MiR143-145 deficiency is associated not only with altered vasocontraction but also with impaired vasodihition, which probably reflects the impaired VSMC differentiation phenotype reported in miR143-145 KO animals.MicroRNAs (miRNAs) are short non-coding RNAs that are involved in the regulation of mRNA expression and protein synthesis (l). miRNAs are implicated in the pathogenesis of various cardiovascular diseases and have also been considered as target for therapeutic intervention (2). Recently, we and others showed that the miR-143/145 cluster regulates vascular smooth muscle cells

Angiotensin II Downregulates MicroRNA-145 to Regulate Kruppel-like Factor 4 and Myocardin Expression in Human Coronary Arterial Smooth Muscle Cells under High Glucose Conditions

“…The findings of the study confirm that miR-145 is an important vasculoprotective miR. Actually, miR-143/145 deficiency impairs vascular function (31). Restoration of miR-145 expression can limit neointimal formation in response to vascular injury by promoting Klf4 downregulation (6).…”

TGFβ Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells, Thereby Modulating Vessel Stabilization

“…45 The miR-143/145 cluster has been observed to play a fundamental role governing SMC differentiation during physiological and pathological events. 8,10,[15][16][17][18] Beside its ability to regulate SMC homeostasis, it is still not well understood how the miR-143/145 cluster regulates EC functions. In this report, we demonstrate that the modulation of the angiogenic potential of ECs is also due to the direct transfer of miR-143/145 from SMCs.…”

“…Other groups, [15][16][17] as well as ours, 8,10,18 have described the role of these miRNAs in the regulation of vascular homeostasis. In particular, we have demonstrated a critical role of the miR-143/145 cluster in SMC differentiation and vascular pathogenesis.…”

MicroRNAs and lipoproteins: A connection beyond atherosclerosis?

“…MiRNAs are implicated in the pathogenesis of various cardiovascular diseases and have also been considered as potential targets for therapeutic intervention [2]. To date, several miRNAs have been described to finely regulate lipid metabolism and the progression and regression of atherosclerosis including miR-122, miR-33, miR-106, miR-758, miR-26, miR-370, miR-378/378*, let-7, miR-27, miR-103, miR-107, miR34a, miR-143 and miR-335 [3–20]. More recently, miRNAs were shown to exert their activities in cells different from those were they have been generated and also systemically.…”