Regulation of microRNA expression in vascular smooth muscle by MRTF-A and actin polymerization

Abstract

The dynamic properties of the actin cytoskeleton in smooth muscle cells play an important role in a number of cardiovascular disease states. The state of actin does not only mediate mechanical stability and contractile function but can also regulate gene expression via myocardin related transcription factors (MRTFs). These transcriptional co-activators regulate genes encoding contractile and cytoskeletal proteins in smooth muscle. Regulation of small noncoding microRNAs (miRNAs) by actin polymerization may mediate some of these effects. MiRNAs are short non-coding RNAs that modulate gene expression by post-transcriptional regulation of target messenger RNA.In this study we aimed to determine a profile of miRNAs that were 1) regulated by actin/MRTF-A, 2) associated with the contractile smooth muscle phenotype and 3) enriched in muscle cells. This analysis was performed using cardiovascular disease-focused miRNA arrays in both mouse and human cells. The potential clinical importance of actin polymerization in aortic aneurysm was evaluated using biopsies from mildly dilated human thoracic aorta in patients with stenotic tricuspid or bicuspid aortic valve.By integrating information from multiple qPCR based miRNA arrays we identified a group of five miRNAs (miR-1, miR-22, miR-143, miR-145 and miR-378a) that were sensitive to actin polymerization and MRTF-A overexpression in both mouse and human smooth muscle. With the exception of miR-22, these miRNAs were also relatively enriched in striated and/or smooth muscle containing tissues. Actin polymerization was found to be dramatically reduced in the aorta from patients with mild aortic dilations. This was associated with a decrease in actin/MRTF-regulated miRNAs.In conclusion, the transcriptional co-activator MRTF-A and actin polymerization regulated a subset of miRNAs in smooth muscle. Identification of novel miRNAs regulated by actin/MRTF-A may provide further insight into the mechanisms underlying vascular disease states, such as aortic aneurysm, as well as novel ideas regarding therapeutic strategies.

Targeting Non-coding RNA in Vascular Biology and Disease

“…Findings in human samples then largely corroborate the hypothesis that the cluster is downregulated in disease, consistent in aortic aneurysm tissue versus control, and in the PBMCs of hypertensive patients ( Elia et al, 2009 ; Kontaraki et al, 2014 ). It has been demonstrated that the process of actin depolymerisation in mild aortic dilation leads to downregulation of miR-143/145 regulated by myocardin-related transcription factors (MRTFs) ( Alajbegovic et al, 2017 ). However, another level of complexity is suggested by conflicting evidence in apparent upregulation in carotid artery plaques of patients with stroke ( Cipollone et al, 2011 ), and similarly higher expression in the carotid plaques of patients with hypertension ( Santovito et al, 2013 ), and pulmonary artery SMCs of patients with pulmonary hypertension ( Caruso et al, 2012 ; Deng et al, 2015 ).…”

Molecular Regulation of Arterial Aneurysms: Role of Actin Dynamics and microRNAs in Vascular Smooth Muscle

“…As a consequence, an increase in G-actin may alter the phenotype of SMCs, from a highly contractile phenotype to a more proliferative phenotype. In a recent study, we have demonstrated that polymerization of actin filaments, and MRTF-dependent gene expression, is reduced in mildly dilated aortas from patients with stenotic tricuspid aortic valve (TAV) or BAV (Alajbegovic et al, 2016 ). This result suggests that altered actin polymerization may be an early event in the development of ascending aortic aneurysm and that the effect is not specific for BAV-associated disease.…”

“…Although miR-29 appears to be particularly promising for therapeutic intervention, additional miRNAs have been demonstrated to be dysregulated in aortic aneurysms, including miR-21 (Maegdefessel et al, 2012a ), miR-26 (Leeper et al, 2011 ), and the miR-143/145 cluster (Elia et al, 2009 ). In a recent study, we demonstrated that a group of smooth muscle miRNAs, including miR-143/145, miR-1, miR-378a, and miR-22, are regulated by actin dynamics via the actin sensitive transcription factor MRTF-A (Alajbegovic et al, 2016 ). With the exception of miR-22, these miRNAs were found to be highly enriched in muscle-containing tissues and downregulated in phenotypically modified SMCs.…”

“…MRTF, myocardin related transcription factor; SRF, serum response factor. Adapted from Alajbegovic et al ( 2016 ).…”

“…Moreover, we have identified a group of miRNAs regulated by actin polymerization and MRTF. Several of these miRNAs are downregulated in dilated aorta suggesting that they may play a role in the development of aneurysms (Alajbegovic et al, 2016 ). In the second part of this Review, we focus on the importance of miRNAs for the formation of arterial aneurysms.…”