Cardioprotective Effects Mediated by Angiotensin II Type 1 Receptor Blockade and Enhancing Angiotensin 1-7 in Experimental Heart Failure in Angiotensin-Converting Enzyme 2–Null Mice
Loss of angiotensin (Ang)-converting enzyme 2 (ACE2) and inability to metabolize Ang II to Ang 1-7 perpetuate the actions of Ang II after biomechanical stress and exacerbate early adverse myocardial remodeling. Ang receptor blockers are known to antagonize the effect of Ang II by blocking Ang II type 1 receptor (AT1R) and also by upregulating the ACE2 expression. We directly compare the benefits of AT1R blockade versus enhancing Ang 1-7 action in pressure-overload–induced heart failure in ACE2 knockout mice. AT1R blockade and Ang 1-7 both resulted in marked recovery of systolic dysfunction in pressure-overloaded ACE2-null mice. Similarly, both therapies attenuated the increase in NADPH oxidase activation by downregulating the expression of Nox2 and p47phox subunits and also by limiting the p47phox phosphorylation. Biomechanical stress-induced increase in protein kinase C-α expression and phosphorylation of extracellular signal–regulated kinase 1/2, signal transducer and activator of transcription 3, Akt, and glycogen synthase kinase 3β were normalized by irbesartan and Ang 1-7. Ang receptor blocker and Ang 1-7 effectively reduced matrix metalloproteinase 2 activation and matrix metalloproteinase 9 levels. Ang II–mediated cellular effects in cultured adult cardiomyocytes and cardiofibrolasts isolated from pressure-overloaded ACE2-null hearts were inhibited to similar degree by AT1R blockade and stimulation with Ang 1-7. Thus, treatment with the AT1R blocker irbesartan and Ang 1-7 prevented the cardiac hypertrophy and improved cardiac remodeling in pressure-overloaded ACE2-null mice by suppressing NADPH oxidase and normalizing pathological signaling pathways.
- renin-angiotensin system
- angiotensin 1-7
- angiotensin-converting enzyme 2
- NADPH oxidase
- AT1 receptor
- heart failure
- Received January 19, 2012.
- Revision received February 8, 2012.
- Accepted March 20, 2012.
- © 2012 American Heart Association, Inc.