Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Cardiovasc Res. 2011 Nov 1;92(2):348-57. doi: 10.1093/cvr/cvr217. Epub 2011 Aug 10.
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.
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.
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.
之前，我们发现慢性心力衰竭（CHF）大鼠室旁核（PVN）内兴奋性（N-甲基-D-天冬氨酸受体-NR（1））增强，抑制性神经元型一氧化氮合酶（nNOS）减少。虽然 NR（1）和 nNOS 通常是相连的，但它们可以通过 nNOS 与 nNOS 相关蛋白（CAPON）结合而分离。本研究旨在阐明 CHF 大鼠 PVN 中 NR（1）表达增加和 nNOS 减少导致交感神经兴奋增强的机制。
CHF 大鼠 PVN 中 CAPON 表达增强，nNOS 表达减少（左冠状动脉结扎后 6-8 周）。CHF 大鼠用血管紧张素 II （Ang II） 1 型受体（AT（1））拮抗剂洛沙坦（Los）治疗可降低肾交感神经活性，并使 PVN 中 CAPON 和 nNOS 的蛋白表达正常化。Los 治疗还逆转了 CHF 大鼠内源性 NO 介导的交感神经抑制作用的减弱。此外，Los 还改善了 Ang II 诱导的 NG108 神经元细胞中 CAPON 表达的增加。
阻断 AT（1）受体可防止 CAPON 过表达和 PVN 中 nNOS 相应减少，从而减弱 CHF 中常见的交感神经兴奋。综上所述，我们的数据强调了 PVN 内 nNOS 和 CAPON 表达改变及其随后相互作用导致 CHF 中交感神经兴奋增加的重要性。确定这种由 AT（1）受体调节的关键 nNOS/CAPON 相互作用可能为 CHF 提供一个重要的潜在治疗靶点。
