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(Hypertension. 2008;51:267.)
© 2008 American Heart Association, Inc.

Original Articles

Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

Sebastien Fuchs; Hong D. Xiao; Christine Hubert; Annie Michaud; Duncan J. Campbell; Jonathan W. Adams; Mario R. Capecchi; Pierre Corvol; Kenneth E. Bernstein

From the Department of Pathology and Laboratory Medicine (S.F., H.D.X., J.W.A., K.E.B.), Emory University School of Medicine, Atlanta, Ga; Institut National de la Sante et de la Recherché Médicale (C.H., A.M., P.C.), Unité 833, Angiogénèse Embryonnaire et Pathologique, Collège de France, Paris, France; St Vincent’s Institute of Medical Research and the Department of Medicine (D.J.C.), University of Melbourne, St Vincent’s Hospital, Fitzroy, Victoria, Australia; and the Howard Hughes Medical Institute (M.R.C.), Eccles Institute of Human Genetics, University of Utah, Salt Lake City.

Correspondence to Sebastien Fuchs, 101 Woodruff Circle, Emory University, Atlanta, GA 30322. E-mail sfuchs{at}emory.edu

Angiotensin-converting enzyme (ACE) plays a central role in the production of the vasoconstrictor angiotensin II. ACE is a single polypeptide, but it contains 2 homologous and independent catalytic domains, each of which binds zinc. To understand the in vivo role of these 2 domains, we used gene targeting to create mice with point mutations in the ACE C-domain zinc-binding motif. Such mice, termed ACE13/13, produce a full-length ACE protein with tissue expression identical to wild-type mice. Analysis of ACE13/13 mice showed that they produce ACE having only N-domain catalytic activity, as determined by the hydrolysis of domain specific substrates and by chloride sensitivity. ACE13/13 mice have blood pressure and blood angiotensin II levels similar to wild-type mice. However, plasma renin concentration is increased 2.6-fold and blood angiotensin I levels are increased 7.5-fold. Bradykinin peptide levels are not different from wild-type levels. ACE13/13 mice have a reduced increase of blood pressure after intravenous infusion of angiotensin I. ACE13/13 mice have a normal renal structure, but they are not able to concentrate urine after dehydration as effectively as wild-type mice. This study shows that the C-domain of ACE is the predominant site of angiotensin I cleavage in vivo. Although mice lacking C-domain activity have normal physiology under laboratory conditions, they respond less well to the stress of dehydration.

Key Words: angiotensin-converting enzyme • angiotensin • blood pressure • male infertility • catalytic sites • bradykinin • genetic mice model

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