title: Candesartan ameliorates cardiac dysfunction observed in angiotensin-converting enzyme 2-deficient mice.
abstract: The renin-angiotensin (Ang) system plays a critical role in the regulation of blood pressure, body fluid, electrolyte homeostasis, and organ remodeling under physiological and pathological conditions. The carboxypeptidase ACE2 is a homologue of angiotensin-converting enzyme (ACE). It has been reported that ACE2-deficient mice develop cardiac dysfunction with increased plasma levels of Ang II. However, the molecular mechanism by which genetic disruption of ACE2 results in heart dysfunction is not fully understood. Here, we generated mice with targeted disruption of the Ace2 gene and compared the cardiovascular function of ACE2(-/y) mice with that of their wild-type littermates. ACE2-deficient mice were viable and fertile and lacked any gross structural abnormalities. Echocardiographic study detected no functional difference between ACE2(-/y) and wild-type mice at 12 weeks of age. Twenty-four-week-old ACE2(-/y) mice displayed significantly enlarged hearts with impaired systolic and diastolic function. The Ang II level was elevated in the plasma and heart of ACE2(-/y) mice. Pharmacological blockade of Ang II type 1 receptor (AT1) with candesartan attenuated the development of cardiac dysfunction in ACE2(-/y) mice. These results suggest that enhanced stimulation of AT1 may play a role in the development of cardiac dysfunction observed in ACE2-deficient mice.
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakamura
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Koibuchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimatsu
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Higashikuni
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kugiyama
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
mesh_terms: D000367:Age Factors; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D006332:Cardiomegaly / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D013777:Tetrazoles; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C081643:candesartan