Yes-Associated Protein Targets the Transforming Growth Factor β Pathway to Mediate High-Fat/High-Sucrose Diet-induced Arterial Stiffness

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 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 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.

The regulation of yes-associated protein/transcriptional coactivator with PDZ-binding motif and their roles in vascular endothelium

“…In addition to the above factors, YAP and TAZ are also regulated by glucose metabolism, hypoxia, and osmotic stress (41,(54)(55)(56)(57)(58)(59)(60)(61)(62). Under normal physiological conditions, YAP promoted glucose metabolism by up-regulating glucose transporter 3.…”

“…Phosphorylation of YAP S127 increased when glucose metabolism was insufficient. On the contrary, in response to high glucose stimulation, YAP was activated and unregulated, and YAP activation led to vascular endothelial inflammation and increased monocyte adhesion (41,(54)(55)(56)(57)(58). In myocardial fibroblasts, high glucose promoted the increase of YAP expression in the nucleus by down-regulating p-MST1 and p-LATS1, resulting in inflammation, cell proliferation, and invasion (59).…”

Knockdown of ubiquitin-conjugating enzyme E2T (UBE2T) suppresses lung adenocarcinoma progression via targeting fibulin-5 (FBLN5)

“…GST-UBE2T protein or GST control was transformed into E. coli BL21, and then 1 mmol/L IPTG was added to induce the protein expression [ 38 ]. Flag-FBLN5 protein was extracted from H1975 cell lysates.…”

Sugar, Fat, and YAP: A Recipe for Vascular Stiffness

“…The identification of exciting new connections between diet, YAP, TGF-β, and stiffness 5 HF/HS diet increases the activation of mTORC1 (mechanistic target of rapamycin complex 1), suppressing autophagy-induced degradation of YAP (Yes-associated protein) in smooth muscle cells (SMC). Increased YAP levels inhibit TGF (transforming growth factor)-βdependent PPM1B (protein phosphatase, Mg 2+ /Mn 2+ -dependent 1B) ubiquitination and translocation to the nucleus.…”

“…The identification of exciting new connections between diet, YAP, TGF-β, and stiffness 5 (Figure) suggests interesting new questions for future investigation. Understanding the long-term effects of HF/HS diet on YAP and TGF-β signaling beyond 8 weeks is important, along with determining whether intermittent exposures (modeling repeated cycles of weight gain and loss) could exacerbate YAP-amplified TGF-β signaling and worsen fibrosis.…”