TWIST1 Drives Smooth Muscle Cell Proliferation in Pulmonary Hypertension via Loss of GATA-6 and BMPR2
Abstract
The basic helix-loop-helix transcription factor TWIST1 controls cell proliferation and differentiation in tissue development and disease processes. Recently, endothelial TWIST1 has been linked to pulmonary hypertension (PH) and endothelial-to-mesenchymal transition, yet the role of TWIST1 in smooth muscle cells remains so far unclear. To define the role of TWIST1 in smooth muscle cells (SMC) in the pathogenesis of PH. SMC-specific TWIST1-deficient mice, SMC-specific TWIST1 silencing in rats, mass spectrometry, immunoprecipitation, and chromatin immunoprecipitation were used to delineate the role of SMC TWIST1 in PH. In pulmonary vessels from PH patients and rodent PH models, TWIST1 expression was markedly increased, and predominantly localized to SMCs. SMC-specific TWIST1 deficiency or silencing attenuated the development of PH and distal vessel muscularization in chronic hypoxic mice and monocrotaline-treated rats. In vitro, TWIST1 inhibition or silencing prevented pulmonary artery SMC proliferation and migration. Mechanistically, the observed effects were mediated, at least in part, by TWIST1-dependent degradation of GATA binding protein 6 (GATA-6). Bone morphogenetic protein receptor-2 (BMPR2) was identified as novel downstr...Continue Reading
References
Twist1 in Hypoxia-induced Pulmonary Hypertension through Transforming Growth Factor-β-Smad Signaling
Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition
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