Decreased nNOS in the PVN leads to increased sympathoexcitation in chronic heart failure: Role for CAPON and Ang II

Neeru M. Sharma, Hong Zheng, Parmender P Mehta, Yi Fan Li, Kaushik P Patel

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Abstract

AimsPreviously, we showed an enhanced excitatory (N-methyl d-aspartate receptor-NR1) and decreased inhibitory neuronal nitric oxide (NO) synthase (nNOS) influence within the paraventricular nucleus (PVN) of rats with chronic heart failure (CHF). Although NR1 and nNOS are normally linked, they can be disconnected by nNOS sequestering with nNOS-associated protein (CAPON). The aim of this study was to elucidate the underlying mechanism for the disconnection between increased expression of NR1 and decreased nNOS in the PVN of rats with CHF which leads to enhanced sympathoexcitation.Methods and resultsCAPON expression was augmented while nNOS expression was decreased in the PVN of rats with CHF (68 weeks after left coronary artery ligation). Angiotensin II (Ang II) type I receptor (AT1) antagonist losartan (Los) treatment in rats with CHF reduced renal sympathetic nerve activity with concomitant normalization of protein expression of CAPON and nNOS in the PVN. Los treatment also reversed the blunting of endogenous NO-mediated sympatho-inhibition in rats with CHF. Moreover, Ang II-induced increase in CAPON expression in NG108 neuronal cells was also ameliorated by Los.ConclusionBlocking AT1 receptors prevents the overexpression of CAPON and concomitant decrease in nNOS in the PVN, resulting in attenuation of sympathoexcitation commonly observed in CHF. Taken together, our data highlight the importance of altered expression and subsequent interaction of nNOS and CAPON within the PVN, leading to increased sympathoexcitation in CHF. Identifying this crucial nNOS/CAPON interaction regulated by AT1 receptors may provide an important potential therapeutic target in CHF.

Original languageEnglish (US)
Pages (from-to)348-357
Number of pages10
JournalCardiovascular research
Volume92
Issue number2
DOIs
Publication statusPublished - Nov 1 2011

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Keywords

  • CAPON
  • Chronic heart failure
  • Paraventricular nucleus
  • Sympathetic nerve activity
  • nNOS

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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