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Statins improve endothelial function via suppression of epigenetic-driven EndMT.
Liu, Chun; Shen, Mengcheng; Tan, Wilson L W; Chen, Ian Y; Liu, Yu; Yu, Xuan; Yang, Huaxiao; Zhang, Angela; Liu, Yanxia; Zhao, Ming-Tao; Ameen, Mohamed; Zhang, Mao; Gross, Eric R; Qi, Lei S; Sayed, Nazish; Wu, Joseph C.
Afiliação
  • Liu C; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Shen M; Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA.
  • Tan WLW; These authors contributed equally: Chun Liu, Mengcheng Shen, Wilson L. W. Tan.
  • Chen IY; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Liu Y; Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA.
  • Yu X; These authors contributed equally: Chun Liu, Mengcheng Shen, Wilson L. W. Tan.
  • Yang H; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Zhang A; Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA.
  • Liu Y; These authors contributed equally: Chun Liu, Mengcheng Shen, Wilson L. W. Tan.
  • Zhao MT; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Ameen M; Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA.
  • Zhang M; Medical Service (Cardiology Section), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
  • Gross ER; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • Qi LS; Department of Medicine (Division of Cardiology), Stanford University, Stanford, CA, USA.
  • Sayed N; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, USA.
  • Wu JC; Department of Biomedical Engineering, University of North Texas, Denton, TX, USA.
Nat Cardiovasc Res ; 2(5): 467-485, 2023 May.
Article em En | MEDLINE | ID: mdl-37693816
ABSTRACT
The pleiotropic benefits of statins in cardiovascular diseases that are independent of their lipid-lowering effects have been well documented, but the underlying mechanisms remain elusive. Here we show that simvastatin significantly improves human induced pluripotent stem cell-derived endothelial cell functions in both baseline and diabetic conditions by reducing chromatin accessibility at transcriptional enhanced associate domain elements and ultimately at endothelial-to-mesenchymal transition (EndMT)-regulating genes in a yes-associated protein (YAP)-dependent manner. Inhibition of geranylgeranyltransferase (GGTase) I, a mevalonate pathway intermediate, repressed YAP nuclear translocation and YAP activity via RhoA signaling antagonism. We further identified a previously undescribed SOX9 enhancer downstream of statin-YAP signaling that promotes the EndMT process. Thus, inhibition of any component of the GGTase-RhoA-YAP-SRY box transcription factor 9 (SOX9) signaling axis was shown to rescue EndMT-associated endothelial dysfunction both in vitro and in vivo, especially under diabetic conditions. Overall, our study reveals an epigenetic modulatory role for simvastatin in repressing EndMT to confer protection against endothelial dysfunction.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Nat Cardiovasc Res Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Nat Cardiovasc Res Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos