FIGURE 11.

Model of miR-199a-5p in smooth muscle differentiation and hypertrophy. Increased expression of miR-199a-5p in smooth muscle cells has two main consequences: it affects WNT signaling by down-regulating WNT2 and influences cytoskeleton remodeling. 1) Inhibition of the WNT signaling pathway leads to down-regulation of KLF4, a WNT-dependent repressor of both myocardin synthesis and transcription of SRF/myocardin (Myocd)-stimulated genes. The KLF4 decrease leads to elevation of myocardin levels; together with SRF, myocardin then induces genes encoding SM-specific and contractile proteins, including SM22, SM α-actin (ACTA2), SM myosin heavy chain (MYH11), and transforming growth factor-β1-induced transcript 1 (TGFB1I1). 2) MiR-199a-5p-regulated cytoskeleton remodeling activates actin-dependent MRTF-A, which translocates to the nucleus, associates with SRF, and stimulates expression of MYL9 and Id3. Id3 is a part of a regulatory network promoting smooth muscle differentiation. The resulting increase in synthesis of contractile and structural proteins leads to SMC hypertrophy.