In vivo transfection of manganese superoxide dismutase gene or nuclear factor κB shRNA in nodose ganglia improves aortic baroreceptor function in heart failure rats.
In vivo transfection of manganese superoxide dismutase gene or nuclear factor κB shRNA in nodose ganglia improves aortic baroreceptor function in heart failure rats.
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DOI：
10.1161/hypertensionaha.113.02057
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Li YL
中科院分区：
文献类型：
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作者：
Zhang D;Liu J;Tu H;Muelleman RL;Cornish KG;Li YL
慢性心力衰竭（CHF）状态下动脉压力反射敏感性降低，与CHF患者心律失常和心源性猝死有关。我们的前期研究表明，CHF引起的压力感受器神经元钠通道功能障碍与CHF大鼠压力反射敏感性减弱有关。线粒体源性超氧化物过量产生降低CHF大鼠压力感受器神经元钠通道的表达和激活。然而，CHF大鼠压力感受器神经元钠通道功能障碍的分子机制尚不清楚。探讨NFκB在CHF大鼠钠通道功能障碍中的作用，以及体内转染锰超氧化物歧化酶基因和NFκB shRNA对CHF大鼠压力感受性反射功能的影响。成年大鼠左冠状动脉结扎后6-8周发生CHF。Western blot和染色质免疫沉淀结果显示，CHF大鼠结状神经节中磷酸化NFκB p65和NFκB p65与钠通道启动子结合的能力增强。体内转染腺病毒锰超氧化物歧化酶基因或慢病毒NFκB p65 shRNA进入结状神经节部分逆转CHF减少的压力感受器神经元钠通道表达和细胞兴奋性，并改善CHF钝化的动脉压力感受器反射敏感性。此外，腺病毒锰超氧化物歧化酶转染还能抑制CHF大鼠结状核神经元磷酸化NFκB p65的增加。目前的研究表明，超氧化物-NF κB信号通路参与CHF诱导的压力感受器功能障碍和压力感受器反射功能的损害。
Arterial baroreflex sensitivity is attenuated in chronic heart failure (CHF) state, which is associated with cardiac arrhythmias and sudden cardiac death in the patients with CHF. Our previous study showed that CHF-induced sodium channel dysfunction in the baroreceptor neurons was involved in the blunted baroreflex sensitivity in CHF rats. Mitochondria-derived superoxide overproduction decreased expression and activation of the sodium channels in the baroreceptor neurons from CHF rats. However, the molecular mechanisms responsible for the sodium channel dysfunction in the baroreceptor neurons from CHF rats remain unknown. We tested the involvement of NFκB in the sodium channel dysfunction and evaluated the effects of in-vivo transfection of manganese superoxide dismutase gene and NFκB shRNA on the baroreflex function in CHF rats. CHF was developed at 6–8 weeks after left coronary artery ligation in adult rats. Western bolt and chromatin immunoprecipitation data showed that phosphorylated NFκB p65 and ability of NFκB p65 binding to the sodium channel promoter were increased in the nodose ganglia from CHF rats. In-vivo transfection of adenoviral manganese superoxide dismutase gene or lentiviral NFκB p65 shRNA into the nodose ganglia partially reversed CHF-reduced sodium channel expression and cell excitability in the baroreceptor neurons and improved CHF-blunted arterial baroreflex sensitivity. Additionally, transfection of adenoviral manganese superoxide dismutase also inhibited the augmentation of phosphorylated NFκB p65 in the nodose neurons from CHF rats. The present study suggests that superoxide-NFκB signaling contributes to CHF-induced baroreceptor dysfunction and resultant impairment of baroreflex function.