MicroRNAs and Smooth Muscle Cells Phenotypic Switching in PAH

Abstract

Smooth muscle cells undergo a switching from contractile phenotype to synthetic phenotype in pulmonary hypertension characterized by excessive proliferation and migration of smooth muscle cells. MicroRNAs are small noncoding RNAs that can negatively regulate gene expression by directly binding with the 3'-UTR of mRNA. Numerous microRNAs have been reported to modulate the smooth muscle cells phenotypic switching and been urged to become possible therapeutic targets for pulmonary hypertension. This review will focus on the roles of microRNAs in regulating smooth muscle cellular phenotypic switching in PAH. MicroRNAs (miRNAs) are a novel class of endogenous, small and non-coding RNAs that function in transcriptional and posttranscriptional regulation of gene expression by directly binding with the 3'-UTR of mRNA [6][7][8]. miRNAs can directly regulate about 30% of the genes in a cell [9], therefore it is not surprising that miRNAs are involved in the regulation of almost all major cellular function, including developmental timing, cell death, cell proliferation [10,11], fat storage [12], haematopoiesis [13][14][15][16][17][18] and patterning of the nervous system [19][20][21][22]. Recent studies have revealed that many non-coding miRNAs can be as novel phenotypic markers and modulators of Vascular Smooth Muscle Cells (VSMCs). These findings display extensive implications for the diagnosis and therapy of a variety of proliferative vascular diseases [23], including PAH. The review will focus on the roles of microRNAs in regulating smooth muscle cellular phenotypic switching in pulmonary hypertension.There are two classic pulmonary hypertension animal models apart induced by monocrotaline (MCT) and hypoxia [24]. In pulmonary hypertension induced by MCT, it usually occurs that endothelial cells damage accompanied with the increasing release of growth factors. PDGF is one of the most common growth factors in PAH and released primarily by vascular endothelial cells and platelets at the sites of vascular injury [25]. Indeed, an increased expression of signaling proteins in the PDGF pathway has been demonstrated in several cardiovascular disorders [26]. Activation of PDGF inhibits smooth muscle cell (SMC)-specific gene expression (SM22α, SM α-actin and calponin) and increases the rate of proliferation and migration, leading to dedifferentiation of VSMCs. Many miRNAs have been demonstrated to play important roles in the stimulation of PDGF with indistinct mechanisms.MiR-15b is shown to be induced by PDGF in pulmonary artery smooth muscle cells and it is critical for the repression of SMC-specific contractile genes [27]. MiR-638 is abundantly expressed in SMCs and markedly down-regulated in the PDGF stimulation. In differentiation medium, miR-638 expression is significantly up-regulated to inhibit SMC proliferation by targeting the orphan nuclear receptor NOR1 [25]. MiR-24 also functions in the process and directly down-regulates Tribbles like protein-3 (Trb3) expression which results in decreased Smad protein levels...