Published Online
on December 24, 2007

A more recent version of this article appeared on February 1, 2008

This Article Full Text (PDF) Data Supplement All Versions of this Article: 51/2/267    most recent HYPERTENSIONAHA.107.097865v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fuchs, S. Articles by Bernstein, K. E. Search for Related Content PubMed PubMed Citation Articles by Fuchs, S. Articles by Bernstein, K. E. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Related Collections ACE/Angiotension receptors

Submitted on July 12, 2007
Revised on August 7, 2007

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; and Kenneth E. Bernstein

Institut National de la Sante et de la Recherché Médicale (C.H., A.M., P.C.), Unité 833, Angiogénèse Embryonnaire et Pathologique, Collége 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.

^* To whom correspondence should be addressed. E-mail: sfuchs{at}emory.edu.

Abstract—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

This article has been cited by other articles:

				K. Zou, T. Maeda, A. Watanabe, J. Liu, S. Liu, R. Oba, Y.-i. Satoh, H. Komano, and M. Michikawa A{beta}42-to-A{beta}40- and Angiotensin-converting Activities in Different Domains of Angiotensin-converting Enzyme J. Biol. Chem., November 13, 2009; 284(46): 31914 - 31920. [Abstract] [Full Text] [PDF]

				X. Liu, C. O. C. Bellamy, M. A. Bailey, L. J. Mullins, D. R. Dunbar, C. J. Kenyon, G. Brooker, S. Kantachuvesiri, K. Maratou, A. Ashek, et al. Angiotensin-converting Enzyme Is a Modifier of Hypertensive End Organ Damage J. Biol. Chem., June 5, 2009; 284(23): 15564 - 15572. [Abstract] [Full Text] [PDF]