Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis

doi:10.1152/ajpheart.00331.2008

Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis

Fina Lovren,¹^,3^,4 Yi Pan,¹^,3^,4^,* Adrian Quan,¹^,3^,4^,* Hwee Teoh,¹^,3^,4 Guilin Wang,¹^,3^,4 Praphulla C. Shukla,¹^,3^,4 Kevin S. Levitt,¹^,3^,4 Gavin Y. Oudit,⁵^,6 Mohammed Al-Omran,³^,11 Duncan J. Stewart,²^,3^,5^,8^,9 Arthur S. Slutsky,³^,5^,10 Mark D. Peterson,¹^,3^,4 Peter H. Backx,⁵^,6^,7^,9 Josef M. Penninger,¹¹ and Subodh Verma¹^,3^,4^,9

¹Division of Cardiac Surgery and ²Cardiology, ³Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; ⁴Departments of Surgery, ⁵Medicine and ⁶Physiology, Division of Cardiology, ⁷University Health Network, ⁸R. Samuel McLaughlin Centre for Molecular and Regenerative Medicine, ⁹Heart and Stroke Richard Lewar Centre of Excellence, ¹⁰Interdepartmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada; ¹¹Division of Vascular Surgery, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia; and ¹²IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria

Submitted 29 March 2008 ; accepted in final form 11 July 2008

The endothelium plays a central role in the maintenance of vascularhomeostasis. One of the main effectors of endothelial dysfunctionis ANG II, and pharmacological approaches to limit ANG II bioactivityremain the cornerstone of cardiovascular therapeutics. Angiotensinconverting enzyme-2 (ACE2) has been identified as a criticalnegative modulator of ANG II bioactivity, counterbalancing theeffects of ACE in determining net tissue ANG II levels; however,the role of ACE2 in the vasculature remains unknown. In thepresent study, we hypothesized that ACE2 is a novel target tolimit endothelial dysfunction and atherosclerosis. To this aim,we performed in vitro gain and loss of function experimentsin endothelial cells and evaluated in vivo angiogenesis andatherosclerosis in apolipoprotein E-knockout mice treated withAdACE2. ACE2-deficient mice exhibited impaired endothelium-dependentrelaxation. Overexpression of ACE2 in human endothelial cellsstimulated endothelial cell migration and tube formation, andlimited monocyte and cellular adhesion molecule expression;effects that were reversed in ACE2 gene silenced and endothelialcells isolated from ACE2-deficient animals. ACE2 attenuatedANG II-induced reactive oxygen species production in part throughdecreasing the expression of p22phox. The effects of ACE2 onendothelial activation were attenuated by pharmacological blockadeof ANG-(1-7) with A779. ACE2 promoted capillary formation andneovessel maturation in vivo and reduced atherosclerosis inapolipoprotein E-knockout mice These data indicate that ACE2,in an ANG-(1-7)-dependent fashion, functions to improve endothelialhomeostasis via a mechanism that may involve attenuation ofNADPHox-induced reactive oxygen species production. ACE2-basedtreatment approaches may be a novel approach to limit aberrantvascular responses and atherothrombosis.

endothelium; atherogenesis; angiogenesis

Address for reprint requests and other correspondence: S. Verma, Division of Cardiac Surgery, St. Michael's Hospital, 8^th Floor Bond Wing, 30 Bond St., Toronto, ON, Canada M5B 1W8 (e-mail: subodh.verma{at}sympatico.ca)