An ACE up your sleeve: 2 is better than 1.

Although the renin angiotensin system (RAS) is a well established regulator of blood pressure and intravascular volume,1 considerable evidence has emerged demonstrating the importance of the RAS directly on the cardiovascular system (please refer to the Figure for description of the enzymatic pathways involved in RAS regulation). Indeed, angiotensin converting enzyme (ACE) inhibitors, which prevent the conversion of angiotensin I into angiotensin II (Ang II), and Ang II receptor type 1 (AT1R) antagonists, which inhibit the receptor-mediated actions of Ang II, have demonstrated direct favorable effects on the heart. These include a reduction in cardiac fibrosis during hypertensive left ventricular (LV) hypertrophy, protection against LV enlargement following myocardial infarction, and reduced LV remodeling following coronary artery bypass graft surgery.2 Hence, ACE1 is generally thought of as a villain contributing to the development of cardiovascular disease due to its generation of Ang II. Fortunately, the RAS may also have a potential hero in ACE2, which can counter many of the negative consequences of ACE1-produced Ang II. In this issue of Circulation Research, Patel et al3 demonstrate an important role for the RAS in the development of diabetic cardiomyopathy. If diabetic Akita mice are deficient for ACE2 (Akita/ ACE2KO), the enzyme responsible for converting Ang II into Ang 1–7, a progressive systolic dysfunction occurred that is associated with oxidative stress, excessive extracellular matrix degradation, vascular dysfunction, and impairment of the Akt-signaling pathway. Ang II activation of the AT1R was implicated in these actions, since a 1-month treatment with the AT1R antagonist, irbesartan, reversed this systolic dysfunction, oxidative stress, vascular dysfunction, and Akt signaling in the Akita/ACE2KO mice.