title: Decreased nNOS in the PVN leads to increased sympathoexcitation in chronic heart failure: role for CAPON and Ang II.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Cellular and Integrative Physiology,  University of Nebraska Medical Center, Omaha, NE 68198-5850,  USA.
authors.forename: Neeru M
authors.initials: NM
authors.lastname: Sharma
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Parmender P
authors.initials: PP
authors.lastname: Mehta
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Li
authors.forename: Kaushik P
authors.initials: KP
authors.lastname: Patel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D007668:Kidney / Q000294:innervation; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D013997:Time Factors; D019323:omega-N-Methylarginine / Q000008:administration & dosage
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047228:Angiotensin II Type 1 Receptor Blockers; D004791:Enzyme Inhibitors; C488082:NOS1AP protein, rat; C409466:NR1 NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D000804:Angiotensin II; D019323:omega-N-Methylarginine; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D019808:Losartan