Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition.

American Journal of Respiratory and Critical Care Medicine
Diana ZabiniWolfgang M Kuebler

Abstract

Vascular remodeling in pulmonary arterial hypertension (PAH) results from smooth muscle cell hypertrophy and proliferation of vascular cells. Loss of BMPR-II (bone morphogenetic protein receptor 2) signaling and increased signaling via TGF-β (transforming growth factor β) and its downstream mediators SMAD (small body size [a C. elegans protein] mothers against decapentaplegic [a Drosophila protein family])-2/3 has been proposed to drive lung vascular remodeling; yet, proteomic analyses indicate a loss of SMAD3 in PAH. We proposed that SMAD3 may be dysregulated in PAH and that loss of SMAD3 may present a pathophysiological master switch by disinhibiting its interaction partner, MRTF (myocardin-related transcription factor), which drives muscle protein expression. SMAD3 levels were measured in lungs from PAH patients, rats treated either with Sugen/hypoxia or monocrotaline (MCT), and in mice carrying a BMPR2 mutation. In vitro, effects of SMAD3 or BMPR2 silencing or SMAD3 overexpression on cell proliferation or smooth muscle hypertrophy were assessed. In vivo, the therapeutic and prophylactic potential of CCG1423, an inhibitor of MRTF, was investigated in Sugen/hypoxia rats. SMAD3 was downregulated in lungs of patients with PAH a...Continue Reading

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Citations

Mar 14, 2018·American Journal of Respiratory and Critical Care Medicine·Evan L BrittainPaul B Yu
Feb 21, 2019·American Journal of Physiology. Lung Cellular and Molecular Physiology·Rui XiaoQinghua Hu
Sep 12, 2018·International Journal of Molecular Sciences·Nina RolMarie-José Goumans
Oct 13, 2018·Journal of Cell Science·David Gau, Partha Roy
Nov 3, 2017·American Journal of Respiratory and Critical Care Medicine·Laszlo Farkas, Martin R J Kolb
May 21, 2019·Journal of Cellular Biochemistry·Lujun Li, Dianming Jiang
Apr 9, 2020·International Journal of Molecular Sciences·Jorge NuchePilar Escribano Subías
Jul 2, 2019·American Journal of Respiratory Cell and Molecular Biology·Laurent CalvierGeorg Hansmann
Jul 22, 2020·American Journal of Respiratory and Critical Care Medicine·Ye FanWolfgang M Kuebler
Aug 21, 2020·The European Respiratory Journal·Christophe Guignabert, Marc Humbert
Jan 20, 2021·American Journal of Respiratory and Critical Care Medicine·Li HuFeng Chen
May 24, 2021·Respiratory Investigation·Bintang TatiusDwi Aris Agung Nugrahaningsih

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Methods Mentioned

BETA
SMA
PCR
FCS
coimmunoprecipitation
pulled
Co-IP
nuclear translocation
transgenic

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