MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury

Abstract

Vascular injury triggers dedifferentiation and cytoskeletal remodeling of smooth muscle cells (SMCs), culminating in vessel occlusion. Serum response factor (SRF) and its coactivator, myocardin, play a central role in the control of smooth muscle phenotypes by regulating the expression of cytoskeletal genes. We show that SRF and myocardin regulate a cardiovascular-specific microRNA (miRNA) cluster encoding miR-143 and miR-145. To assess the functions of these miRNAs in vivo, we systematically deleted them singly and in combination in mice. Mice lacking both miR-143 and miR-145 are viable and do not display overt abnormalities in smooth muscle differentiation, although they show a significant reduction in blood pressure due to reduced vascular tone. Remarkably, however, neointima formation in response to vascular injury is profoundly impeded in mice lacking these miRNAs, due to disarray of actin stress fibers and diminished migratory activity of SMCs. These abnormalities reflect the regulation of a cadre of modulators of SRF activity and actin dynamics by miR-143 and miR-145. Thus, miR-143 and miR-145 act as integral components of the regulatory network whereby SRF controls cytoskeletal remodeling and phenotypic switching of SMCs during vascular disease.

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

“…43 The results classify miR-199a-5p in the same family of SRF-regulated muscle miRNAs (or myomiRs) miR-1, miR133a/b, miR-143, miR-145, miR-206, and miR-486. [44][45][46][47][48] Additionally, they suggest a SRF/MRTF-dependent mechanism for the induction of miR-199a-5p transcription and subsequent downregulation of WNT signaling to allow for normal myogenic differentiation to occur (Figure 7h). Another factor capable of binding to the same CArG box DNA-binding site as SRF, Yin-Yang 1, is highly expressed in MB and is displaced from muscle structural gene promoters during myogenic differentiation.…”

Age‐related changes in miR‐143‐3p:Igfbp5 interactions affect muscle regeneration

“…In other tissues, miR‐143 impairs glucose metabolism through the induction of insulin resistance (Jordan et al ., 2011), regulates the contractility and maintenance of smooth muscle myoblasts (Elia et al ., 2009) and controls vascular remodelling following injury (Xin et al ., 2009) and intestinal epithelial regeneration (Chivukula et al ., 2014). …”

“…miR‐143‐3p (miR‐143) has an established role in the function of smooth muscle myoblasts and adipogenesis (Esau et al ., 2004; Cordes et al ., 2009; Elia et al ., 2009; Xin et al ., 2009). miR‐143‐5p is highly expressed in skeletal muscle tissue, and its expression is downregulated during aging (Kim et al ., 2014).…”

Role of serum response factor in the pathogenesis of disease

“…23,37 Although SRF is not considered to be a direct repressor of gene expression, it may indirectly silence gene activity through its ability to bind to and activate CArG-containing miRs. 25,40,41 In fact, some upregulated genes in SRF-null cardiomyocytes have been shown to increase because of the loss in the expression of SRF-dependent miRs that normally limit such gene expression. 37 Sustained elevated levels of SRF in a single transgenic mouse line carrying human SRF under control of the Myh6 promoter resulted in cardiomyopathy characterized by fourchamber dilatation, myocyte hypertrophy, interstitial fibrosis, and mitochondrial/myofiber damage.…”