Maohuan Lin1,2, Woliang Yuan1,2, Zizhuo Su1,2, Caina Lin3, Tucheng Huang1,2, Yangxin Chen1,2, Jingfeng Wang1,2. 1. Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China. 2. Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. 3. Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China.
Abstract
OBJECTIVES: Yes-associated protein (YAP) has been reported to regulate cell proliferation and differentiation. We aimed to characterize the role of YAP in angiotensin II (Ang II)-induced hypertensive vascular remodelling (HVR) and vascular smooth muscle cells (VSMCs) phenotypic modulation and to explore the underlying mechanisms. MATERIALS AND METHODS: An HVR rat model was established by continuous Ang II infusion for 2 weeks. Western blotting, qRT-PCR, and confocal microscopy were conducted to assess YAP expression. YAP-shRNA interfering plasmid and adenovirus were constructed to knock down YAP. We used cell proliferation and migration assays, accompanied by pathway inhibitors, to evaluate the biological function and underlying mechanisms. RESULTS: Ang II upregulated YAP expression in the media of carotid artery; however, in vivo YAP silencing significantly mitigated HVR, independent of the blood pressure level. Ang II upregulated YAP expression and promoted YAP nuclear accumulation in a dose- and time-dependent manner in rat VSMCs. YAP knockdown ameliorated Ang II-induced VSMCs phenotypic modulation. The regulation of YAP by Ang II could be blocked by pretreatment with angiotensin receptor type 1 antagonist losartan or F-actin depolymerizing agent latrunculin B but not the AT2R antagonist PD 123319. Disrupting the YAP-TEA domain (TEAD) interaction with verteporfin inhibited Ang II-induced VSMCs phenotypic modulation. CONCLUSIONS: Yes-associated protein mediated angiotensin II-induced VSMCs phenotypic modulation and vascular remodelling. YAP is a potential therapeutic target for HVR beyond blood pressure control.
OBJECTIVES:Yes-associated protein (YAP) has been reported to regulate cell proliferation and differentiation. We aimed to characterize the role of YAP in angiotensin II (Ang II)-induced hypertensive vascular remodelling (HVR) and vascular smooth muscle cells (VSMCs) phenotypic modulation and to explore the underlying mechanisms. MATERIALS AND METHODS: An HVR rat model was established by continuous Ang II infusion for 2 weeks. Western blotting, qRT-PCR, and confocal microscopy were conducted to assess YAP expression. YAP-shRNA interfering plasmid and adenovirus were constructed to knock down YAP. We used cell proliferation and migration assays, accompanied by pathway inhibitors, to evaluate the biological function and underlying mechanisms. RESULTS:Ang II upregulated YAP expression in the media of carotid artery; however, in vivo YAP silencing significantly mitigated HVR, independent of the blood pressure level. Ang II upregulated YAP expression and promoted YAP nuclear accumulation in a dose- and time-dependent manner in rat VSMCs. YAP knockdown ameliorated Ang II-induced VSMCs phenotypic modulation. The regulation of YAP by Ang II could be blocked by pretreatment with angiotensin receptor type 1 antagonist losartan or F-actin depolymerizing agent latrunculin B but not the AT2R antagonist PD 123319. Disrupting the YAP-TEA domain (TEAD) interaction with verteporfin inhibited Ang II-induced VSMCs phenotypic modulation. CONCLUSIONS:Yes-associated protein mediated angiotensin II-induced VSMCs phenotypic modulation and vascular remodelling. YAP is a potential therapeutic target for HVR beyond blood pressure control.
Authors: Lars H Lindholm; Hans Ibsen; Björn Dahlöf; Richard B Devereux; Gareth Beevers; Ulf de Faire; Frej Fyhrquist; Stevo Julius; Sverre E Kjeldsen; Krister Kristiansson; Ole Lederballe-Pedersen; Markku S Nieminen; Per Omvik; Suzanne Oparil; Hans Wedel; Peter Aurup; Jonathan Edelman; Steven Snapinn Journal: Lancet Date: 2002-03-23 Impact factor: 79.321
Authors: Eric Miller; Jiayi Yang; Michael DeRan; Chunlei Wu; Andrew I Su; Ghislain M C Bonamy; Jun Liu; Eric C Peters; Xu Wu Journal: Chem Biol Date: 2012-08-09