Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: A positive feedback mechanism in the RAS

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• 作者：Vaibhav B. Patel ; Nicola Clarke ; Zuocheng Wang ; Dong Fan ; Nirmal Parajuli ; Ratnadeep Basu ; Brendan Putko ; Zamaneh Kassiri ; Anthony J. Turner ; Gavin Y. Oudit
• 关键词：ACE ; angiotensin converting enzyme ; Ang ; angiotensin ; AT1R ; angiotensin II type 1 receptor ; HF ; heart failure ; KO ; knockout ; p38 MAPK ; p38 mitogen activated protein kinase ; RAS ; renin&ndash ; angiotensin system ; ROS ; reactive oxygen species ; TACE ; tumor necrosis factor-伪 converting enzyme
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：January, 2014
• 年：2014
• 卷：66
• 期：Complete
• 页码：167-176
• 全文大小：1978 K

文摘

Angiotensin converting enzyme (ACE) 2 is a key negative regulator of the renin-angiotensin system where it metabolizes angiotensin (Ang) II into Ang 1-7. We hypothesize that Ang II suppresses ACE2 by increasing TNF-伪 converting enzyme (TACE) activity and ACE2 cleavage. Ang II infusion (1.5 mg/kg/day) in wild-type mice for 2 weeks resulted in substantial decrease in myocardial ACE2 protein levels and activity with corresponding increase in plasma ACE2 activity, prevented by AT1R blockade. Ang II resulted in AT1R-mediated increase in myocardial TACE expression and activity, and membrane translocation of TACE. Ang II treatment in Huh7 cells exhibited AT1R-dependent metalloproteinase mediated shedding of ACE2 while transfection with siTACE prevented shedding of ACE2; cardiomyocyte-specific deletion of TACE also prevented shedding of ACE2. Reactive oxygen species played a key role since p47^phoxKO mice were resistant to Ang II-induced TACE phosphorylation and activation with preservation of myocardial ACE2 which dampened Ang II-induced cardiac dysfunction and hypertrophy. In conclusion, Ang II induces ACE2 shedding by promoting TACE activity as a positive feedback mechanism whereby Ang II facilitates the loss of its negative regulator, ACE2. In HF, elevated plasma ACE2 activity likely represents loss of the protective effects of ACE2 in the heart.