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Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2402-12. doi: 10.1152/ajpheart.00330.2011. Epub 2011 Sep 30.

Angiotensin-converting enzyme 2 overexpression improves central nitric oxide-mediated sympathetic outflow in chronic heart failure.

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  • 1Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, 68198-5850, USA.


Angiotensin (ANG)-converting enzyme (ACE)2 in brain regions such as the paraventricular nucleus (PVN) controlling cardiovascular function may be involved in the regulation of sympathetic outflow in chronic heart failure (CHF). The purpose of this study was to determine if ACE2 plays a role in the central regulation of sympathetic outflow by regulating neuronal nitric oxide (NO) synthase (nNOS) in the PVN. We investigated ACE2 and nNOS expression within the PVN of rats with CHF. We then determined the effects of ACE2 gene transfer in the PVN on the contribution of NO-mediated sympathoinhibition in rats with CHF. The results showed that there were decreased expressions for ACE2, the ANG-(1-7) receptor, and nNOS within the PVN of rats with CHF. After the application of adenovirus vectors encoding ACE2 (AdACE2) into the PVN, the increased expression of ACE2 in the PVN was confirmed by Western blot analysis. AdACE2 transfection significantly increased nNOS protein levels (change of 50 ± 5%) in the PVN of CHF rats. In anesthetized rats, AdACE2 treatment attenuated the responses of renal sympathetic nerve activity (RSNA), mean arterial pressure, and heart rate to the NOS inhibitor N-monomethyl-L-arginine in rats with CHF (RSNA: 28 ± 3% vs. 16 ± 3%, P < 0.05) compared with CHF + AdEGFP group. Furthermore, neuronal NG-108 cells incubated with increasing doses of AdACE2 showed a dose-dependent increase in nNOS protein expression (60% at the highest dose). Taken together, our data highlight the importance of increased expression and subsequent interaction of ACE2 and nNOS within the PVN, leading to a reduction in sympathetic outflow in the CHF condition.

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