Deletion of Angiotensin-Converting Enzyme 2 Accelerates Pressure Overload-Induced Cardiac Dysfunction by Increasing Local Angiotensin II

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Abstract
Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that cleaves angiotensin II to angiotensin 1-7. Recently, it was reported that mice lacking ACE2 (ACE2−/y mice) exhibited reduced cardiac contractility. Because mechanical pressure overload activates the cardiac renin-angiotensin system, we used ACE2−/y mice to analyze the role of ACE2 in the response to pressure overload. Twelve-week-old ACE2−/y mice and wild-type (WT) mice received transverse aortic constriction (TAC) or sham operation. Sham-operated ACE2−/y mice exhibited normal cardiac function and had morphologically normal hearts. In response to TAC, ACE2−/y mice developed cardiac hypertrophy and dilatation. Furthermore, their hearts displayed decreased cardiac contractility and increased fetal cardiac gene induction, compared with WT mice. In response to chronic pressure overload, ACE2−/y mice developed pulmonary congestion and increased incidence of cardiac death compared with WT mice. On a biochemical level, cardiac angiotensin II conce...