Angiotensin-converting enzyme C-terminal catalytic domain is the main site of angiotensin I cleavage in vivo

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

来源：Hypertension, 2008, 51(2): 267-274.

DOI：10.1161/HYPERTENSIONAHA.107.097865

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

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.

• 出版日期2008-2-1
• 单位河北医科大学