Gene transfer of angiotensin converting enzyme 2 to the paraventricular nucleus improves attenuated nitric oxide mechanism in rats with chronic heart failure

Abstract

In the present study, we investigated the effects of angiotensin converting enzyme 2 (ACE2) gene transfer on nitric oxide (NO) mechanism contributed to the elevated sympathoexcitation in the rats with coronary ligation model of chronic heart failure (CHF). Adenovirus vectors encoding either ACE2 (AdACE2) or EGFP (AdEGFP) were transfered into the paraventricular nucleus (PVN) in vivo. 3 days after application of AdACE2, the expression of ACE2 in the PVN was confirmed by immunohistochemistry. In alpha‐chloralose and urethane anesthetized rats, AdACE2 significantly improved the attenuated renal sympathetic nerve activity (RSNA), blood pressure (BP) and heart rate (HR) responses to neuronal NO synthase (nNOS) inhibitor L‐NMMA in the rats with CHF (RSNA: 29±5% vs 10±1%, P<0.05) compared to CHF‐AdEGFP group. AdACE2 transfection significantly normalized the decreased nNOS protein levels (Δ30±4%) in the PVN in CHF rats. Furthermore, neuronal NG‐108 cells were stimulated with AdACE2 or AdEGFP in a dose‐dependent manner. nNOS protein expression increased in a dose‐dependent manner after AdACE2 transfection. The highest dose showed an approximately 50% increase in nNOS protein expression compared to the control dose. We conclude that the up‐regulation of ACE2 by gene transfer significantly stimulates nNOS production and the effects of ACE2 on the NO mechanism in the PVN may play an important role in the altered balance and tone of sympathetic outflow in the CHF condition.