Silencing nox4 in the paraventricular nucleus improves myocardial infarction-induced cardiac dysfunction by attenuating sympathoexcitation and periinfarct apoptosis.
Silencing nox4 in the paraventricular nucleus improves myocardial infarction-induced cardiac dysfunction by attenuating sympathoexcitation and periinfarct apoptosis.
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DOI：
10.1161/circresaha.109.213025
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发表时间：
2010-06-11
影响因子：
20.1
通讯作者：
Davisson RL
中科院分区：
文献类型：
--
作者：
Infanger DW;Cao X;Butler SD;Burmeister MA;Zhou Y;Stupinski JA;Sharma RV;Davisson RL
心肌梗死（MI）引起的心力衰竭（HF）以中枢神经系统（CNS）驱动的交感神经兴奋和心脏功能恶化为特征。下丘脑的室旁核（PVN）是交感神经活动的关键调节器，并与HF有关。PVN和其他CNS位点中的氧化还原信号传导是神经-心血管调节的主要机制，并且通过激活NADPH氧化酶（Nox）产生过量的氧化剂与一些神经-心血管疾病有关。我们测试了这一假设，即在PVN的NOx介导的氧化还原信号有助于MI诱导的交感神经兴奋和心脏功能障碍的小鼠。Real-time PCR结果显示，在基础培养条件下，Nox 4在PVN中的表达量最高。冠状动脉结扎（MI）引起的选择性上调这一同源物相比，Nox 1和Nox 2。腺病毒基因转移Nox 4 siRNA（AdsiNox 4）PVN（双边）衰减MI诱导的超氧化物形成在这个大脑区域（第14天）的PVN靶向基因转移细胞质超氧化物歧化酶（AdCu/ZnSOD）产生的水平相同。通过超声心动图和左心室血流动力学分析评估，在PVN中用AdsiNox 4或AdCu/ZnSOD治疗的MI小鼠显示心脏功能显著改善。这是伴随着显着减少交感神经流出和细胞凋亡的周围梗死区的心脏。这些结果表明，心肌梗死引起室旁核中Nox 4介导的氧化还原信号转导失调，导致交感神经过度激活和心脏功能下降。靶向抑制PVN中的氧化剂信号传导可以为MI诱导的HF提供新的治疗。
Myocardial infarction (MI)-induced heart failure (HF) is characterized by central nervous system (CNS)-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in HF. Redox signaling in the PVN and other CNS sites is a primary mechanism of neuro-cardiovascular regulation, and excessive oxidant production by activation of NADPH oxidases (Nox) is implicated in some neuro-cardiovascular diseases. We tested the hypothesis that Nox-mediated redox signaling in the PVN contributes to MI-induced sympathoexcitation and cardiac dysfunction in mice. Real-time PCR revealed that Nox4 was the most abundantly expressed Nox in PVN under basal conditions. Coronary arterial ligation (MI) caused a selective upregulation of this homologue compared to Nox1 and Nox2. Adenoviral gene transfer of Nox4 siRNA (AdsiNox4) to PVN (bilateral) attenuated MI-induced superoxide formation in this brain region (day 14) to the same level as that produced by PVN-targeted gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD). MI mice treated with AdsiNox4 or AdCu/ZnSOD in the PVN showed marked improvement in cardiac function as assessed by echocardiography and left ventricular hemodynamic analysis. This was accompanied by significantly diminished sympathetic outflow and apoptosis in the peri-infarct region of the heart. These results suggest that MI causes dysregulation of Nox4-mediated redox signaling in the PVN, which leads to sympathetic overactivation and a decline in cardiac function. Targeted inhibition of oxidant signaling in the PVN could provide a novel treatment for MI-induced HF.