Yes-Associated Protein Targets the Transforming Growth Factor β Pathway to Mediate High-Fat/High-Sucrose Diet-induced Arterial Stiffness. Issue 6 (18th March 2022)

• Record Type: Journal Article
• Authors: Liu, Yanan; Li, Mengke; Lv, Xue; Bao, Kaiwen; Yu Tian, Xiao; He, Lei; Shi, Lei; Zhu, Yi; Ai, Ding
• Is Part Of: Circulation research. Volume 130:Issue 6(2022)
• Publication Date: 2022-03-18
• Subjects: cardiovascular disease -- diet -- metabolic syndrome -- mice -- sucrose; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.121.320464
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Background: Metabolic syndrome is related to cardiovascular diseases, which is attributed in part, to arterial stiffness; however, the mechanisms remain unclear. The present study aimed to investigate the molecular mechanisms of metabolic syndrome–induced arterial stiffness and to identify new therapeutic targets. Methods: Arterial stiffness was induced by high-fat/high-sucrose diet in mice, which was quantified by Doppler ultrasound. Four-dimensional label-free quantitative proteomic analysis, affinity purification and mass spectrometry, and immunoprecipitation and GST (glutathione S-transferase) pull-down experiments were performed to explore the mechanism of YAP (Yes-associated protein)-mediated TGF (transforming growth factor) β pathway activation. Results: YAP protein was upregulated in the aortic tunica media of mice fed a high-fat/high-sucrose diet for 2 weeks and precedes arterial stiffness. Smooth muscle cell–specific YAP knockdown attenuated high-fat/high-sucrose diet–induced arterial stiffness and activation of TGFβ-Smad2/3 signaling pathway in arteries. By contrast, Myh11Cre ERT2 -Yap Tg mice exhibited exacerbated high-fat/high-sucrose diet–induced arterial stiffness and enhanced TGFβ-activated Smad2/3 phosphorylation in arteries. PPM1B (protein phosphatase, Mg 2+ /Mn 2+ -dependent 1B) was identified as a YAP-bound phosphatase that translocates into the nucleus to dephosphorylate Smads (mothers against decapentaplegic homologs) in response to TGFβ. This process was inhibited by YAP through removal of the K63-linked ubiquitin chain of PPM1B at K326. Conclusions: This study provides a new mechanism by which smooth muscle cell YAP regulates the TGFβ pathway and a potential therapeutic target in metabolic syndrome–associated arterial stiffness. Abstract : Supplemental Digital Content is available in the text.