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Decreased nNOS in the PVN leads to increased sympathoexcitation in chronic heart failure: role for CAPON and Ang II.
Cardiovasc Res. 2011 Nov 01; 92(2):348-57.CR

Abstract

AIMS

Previously, we showed an enhanced excitatory (N-methyl d-aspartate receptor-NR(1)) and decreased inhibitory neuronal nitric oxide (NO) synthase (nNOS) influence within the paraventricular nucleus (PVN) of rats with chronic heart failure (CHF). Although NR(1) 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 NR(1) and decreased nNOS in the PVN of rats with CHF which leads to enhanced sympathoexcitation.

METHODS AND RESULTS

CAPON expression was augmented while nNOS expression was decreased in the PVN of rats with CHF (6-8 weeks after left coronary artery ligation). Angiotensin II (Ang II) type I receptor (AT(1)) 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.

CONCLUSION

Blocking AT(1) 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 AT(1) receptors may provide an important potential therapeutic target in CHF.

Authors+Show Affiliations

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21831995

Citation

Sharma, Neeru M., et al. "Decreased nNOS in the PVN Leads to Increased Sympathoexcitation in Chronic Heart Failure: Role for CAPON and Ang II." Cardiovascular Research, vol. 92, no. 2, 2011, pp. 348-57.
Sharma NM, Zheng H, Mehta PP, et al. Decreased nNOS in the PVN leads to increased sympathoexcitation in chronic heart failure: role for CAPON and Ang II. Cardiovasc Res. 2011;92(2):348-57.
Sharma, N. M., Zheng, H., Mehta, P. P., Li, Y. F., & Patel, K. P. (2011). Decreased nNOS in the PVN leads to increased sympathoexcitation in chronic heart failure: role for CAPON and Ang II. Cardiovascular Research, 92(2), 348-57. https://doi.org/10.1093/cvr/cvr217
Sharma NM, et al. Decreased nNOS in the PVN Leads to Increased Sympathoexcitation in Chronic Heart Failure: Role for CAPON and Ang II. Cardiovasc Res. 2011 Nov 1;92(2):348-57. PubMed PMID: 21831995.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Decreased nNOS in the PVN leads to increased sympathoexcitation in chronic heart failure: role for CAPON and Ang II. AU - Sharma,Neeru M, AU - Zheng,Hong, AU - Mehta,Parmender P, AU - Li,Yi-Fan, AU - Patel,Kaushik P, Y1 - 2011/08/10/ PY - 2011/8/12/entrez PY - 2011/8/13/pubmed PY - 2012/2/2/medline SP - 348 EP - 57 JF - Cardiovascular research JO - Cardiovasc. Res. VL - 92 IS - 2 N2 - AIMS: Previously, we showed an enhanced excitatory (N-methyl d-aspartate receptor-NR(1)) and decreased inhibitory neuronal nitric oxide (NO) synthase (nNOS) influence within the paraventricular nucleus (PVN) of rats with chronic heart failure (CHF). Although NR(1) 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 NR(1) and decreased nNOS in the PVN of rats with CHF which leads to enhanced sympathoexcitation. METHODS AND RESULTS: CAPON expression was augmented while nNOS expression was decreased in the PVN of rats with CHF (6-8 weeks after left coronary artery ligation). Angiotensin II (Ang II) type I receptor (AT(1)) 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. CONCLUSION: Blocking AT(1) 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 AT(1) receptors may provide an important potential therapeutic target in CHF. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/21831995/Decreased_nNOS_in_the_PVN_leads_to_increased_sympathoexcitation_in_chronic_heart_failure:_role_for_CAPON_and_Ang_II_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvr217 DB - PRIME DP - Unbound Medicine ER -