Candesartan Ameliorates Cardiac Dysfunction Observed in Angiotensin-Converting Enzyme 2-Deficient Mice

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 carboxy-peptidase 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–ly 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–ly and wild-type mice at 12 weeks of age. Twenty-four-week-old ACE2–ly mice displayed significantly enlarged hearts with impaired systolic and diastolic function. The Ang II level was elevated in the plasma and heart of ACE2–ly mice. Pharmacological blockade of Ang II type 1 receptor (AT1) with candesartan attenuated the development of cardiac dysfunction in ACE2–ly mice. These results suggest that enhanced stimulation of AT1 may play a role in the development of cardiac dysfunction observed in ACE2-deficient mice.

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