LncRNA MYOSLID contributes to PH via targeting BMPR2 signaling in pulmonary artery smooth muscle cell.

The pathogenesis and vascular remodeling during pulmonary hypertension (PH) have been associated with dysregulation of bone morphogenetic protein receptor type 2 (BMPR2) and transforming growth factor-β (TGF-β) signaling in pulmonary artery smooth muscle cells (PASMCs). Evidence suggests that the human-specific lncRNA MYOSLID is a transcriptional target of the TGF-β/SMAD pathway. In this study, we investigated the involvement of MYOSLID in the pathogenesis of PH. Lung tissues from PH patients and rat PH models were analyzed to assess clinical relevance. RNA-Seq was performed to identify target genes. Pulmonary artery smooth muscle cells (PASMCs) were used to evaluate function and underlying mechanisms. RNA-Seq analysis of PASMCs stimulated by TGF-β1 revealed significantly dysregulated lncRNAs. MYOSLID expression was markedly elevated in lung tissues from PH patients and in PASMCs stimulated with TGF-β1. Mechanistically, loss of MYOSLID inhibited the TGF-β pathway by reducing SMAD2/3 PHosphorylation and activated the BMPR2 pathway by enhancing SMAD1/5/9 phosphorylation and increasing ID genes expression in PASMCs. DAZAP2, a target gene of MYOSLID, functions as an inhibitor of BMPR2 signaling. Moreover, DAZAP2 expression was significantly elevated in lung tissues from PH patients and rat PH models. Functionally, knockdown of MYOSLID and DAZAP2 reduced proliferation, migration, and apoptosis resistance in PASMCs. The activation of the MYOSLID-DAZAP2-BMPR2 axis contributes to pulmonary vascular remodeling, and targeting MYOSLID and DAZAP2 may represent novel therapeutic strategies for PH treatment.

Chen Y ，Li Y ，Leng B ，Cao C ，Wu G ，Ye S ，Deng L ... -  《-》

MYOSLID Is a Novel Serum Response Factor-Dependent Long Noncoding RNA That Amplifies the Vascular Smooth Muscle Differentiation Program.

Long noncoding RNAs (lncRNA) represent a growing class of noncoding genes with diverse cellular functions. We previously reported on SENCR, an lncRNA that seems to support the vascular smooth muscle cell (VSMC) contractile phenotype. However, information about the VSMC-specific lncRNAs regulated by myocardin (MYOCD)/serum response factor, the master switch for VSMC differentiation, is unknown. To define novel lncRNAs with functions related to VSMC differentiation, we performed RNA sequencing in human coronary artery SMCs that overexpress MYOCD. Several novel lncRNAs showed altered expression with MYOCD overexpression and one, named MYOcardin-induced Smooth muscle LncRNA, Inducer of Differentiation (MYOSLID), was activated by MYOCD and selectively expressed in VSMCs. MYOSLID was a direct transcriptional target of both MYOCD/serum response factor and transforming growth factor-β/SMAD pathways. Functional studies revealed that MYOSLID promotes VSMC differentiation and inhibits VSMC proliferation. MYOSLID showed reduced expression in failed human arteriovenous fistula samples compared with healthy veins. Although MYOSLID did not affect gene expression of transcription factors, such as serum response factor and MYOCD, its depletion in VSMCs disrupted actin stress fiber formation and blocked nuclear translocation of MYOCD-related transcription factor A (MKL1). Finally, loss of MYOSLID abrogated transforming growth factor-β1-induced SMAD2 phosphorylation. We have demonstrated that MYOSLID, the first human VSMC-selective and serum response factor/CArG-dependent lncRNA, is a novel modulator in amplifying the VSMC differentiation program, likely through feed-forward actions of both MKL1 and transforming growth factor-β/SMAD pathways.

Zhao J ，Zhang W ，Lin M ，Wu W ，Jiang P ，Tou E ，Xue M ，Richards A ，Jourd'heuil D ，Asif A ，Zheng D ，Singer HA ，Miano JM ，Long X ... -  《-》

BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension.

Shen H ，Gao Y ，Ge D ，Tan M ，Yin Q ，Wei TW ，He F ，Lee TY ，Li Z ，Chen Y ，Yang Q ，Liu Z ，Li X ，Chen Z ，Yang Y ，Zhang Z ，Thistlethwaite PA ，Wang J ，Malhotra A ，Yuan JX ，Shyy JY ，Gong K ... -  《-》

BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines.

Davies RJ ，Holmes AM ，Deighton J ，Long L ，Yang X ，Barker L ，Walker C ，Budd DC ，Upton PD ，Morrell NW ... -  《-》

Transforming growth factor-β(1) represses bone morphogenetic protein-mediated Smad signaling in pulmonary artery smooth muscle cells via Smad3.

Upton PD ，Davies RJ ，Tajsic T ，Morrell NW ... -  《-》