The Second Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, P. R. China.
Shanxi Province Cardiovascular Hospital, Taiyuan, 030024, Shanxi, P. R. China.
Exp Physiol. 2019 Nov;104(11):1638-1649. doi: 10.1113/EP087552. Epub 2019 Oct 10.
What is the central question of this study? Does NADPH oxidase activation mediate cardiac sympathetic nerve denervation and dysfunction in heart failure. What is the main findings and its importance? Cardiac sympathetic nerve terminal density and function were reduced in heart failure after myocardial infarction in rabbits. The NADPH oxidase inhibitor apocynin prevented the reduction in cardiac sympathetic nerve terminal density and function in heart failure. This suggest that NADPH oxidase activation mediates cardiac sympathetic nerve terminal abnormalities in heart failure. NADPH oxidase may be a potential therapeutic target for cardiac sympathetic denervation and dysfunction in heart failure.
Congestive heart failure (CHF) is characterized by cardiac sympathetic nerve terminal abnormalities, as evidenced by decreased noradrenaline transporter (NAT) density and cardiac catecholaminergic and tyrosine hydroxylase (TH) profiles. These alterations are associated with increased reactive oxygen species (ROS). NADPH oxidase is a major source of ROS in CHF. In this study, we tested the hypothesis that NADPH oxidase activation mediates cardiac sympathetic nerve terminal abnormalities in CHF. CHF was produced by myocardial infarction (MI) in rabbits. Rabbits with MI or a sham operation were randomized to orally receive an NADPH oxidase inhibitor, apocynin (6 mg kg day ), or placebo for 30 days. MI rabbits exhibited left ventricular dilatation, systolic dysfunction, and increases in NADPH oxidase activity and 4-hydroxynonenal expression in the remote non-infarcted myocardium, all of which were prevented by treatment with apocynin. Cardiac catecholaminergic histofluorescence profiles and immunostained TH and PGP9.5 expression were decreased, and the decreases were ameliorated by apocynin treatment. NAT, TH and PGP9.5 protein and mRNA expression were reduced and the reduction was mitigated by apocynin treatment. The effects of apocynin were confirmed by utilizing the NADPH oxidase inhibitor diphenyleneiodonium in a separate experiment. In conclusion, the NADPH oxidase inhibitor apocynin attenuated increased myocardial oxidative stress and decreased cardiac sympathetic nerve terminals in CHF after MI in rabbits. These findings suggest that the activation of NADPH oxidase mediates cardiac sympathetic nerve terminal abnormalities in CHF, and the inhibition of NADPH oxidase may be beneficial for the treatment of heart failure.
本研究的核心问题是什么？NADPH 氧化酶激活是否介导心力衰竭中心肌交感神经去神经和功能障碍。主要发现及其重要性是什么？在兔心肌梗死后心力衰竭中，心脏交感神经末梢密度和功能降低。NADPH 氧化酶抑制剂 apocynin 可预防心力衰竭中心肌交感神经末梢密度和功能的降低。这表明 NADPH 氧化酶激活介导心力衰竭中心肌交感神经末梢异常。NADPH 氧化酶可能是心力衰竭中心肌交感神经去神经和功能障碍的潜在治疗靶点。
充血性心力衰竭（CHF）的特征是心脏交感神经末梢异常，表现为去甲肾上腺素转运体（NAT）密度降低以及心脏儿茶酚胺和酪氨酸羟化酶（TH）谱降低。这些改变与活性氧物种（ROS）增加有关。NADPH 氧化酶是 CHF 中 ROS 的主要来源。在这项研究中，我们测试了 NADPH 氧化酶激活是否介导 CHF 中心肌交感神经末梢异常的假设。通过心肌梗死（MI）在兔中产生 CHF。MI 或假手术的兔子被随机口服 NADPH 氧化酶抑制剂 apocynin（6mg/kg/天）或安慰剂 30 天。MI 兔表现出左心室扩张、收缩功能障碍以及远程非梗塞心肌中 NADPH 氧化酶活性和 4-羟基壬烯醛表达增加，这些均被 apocynin 治疗所预防。心脏儿茶酚胺荧光组织化学图谱以及免疫染色 TH 和 PGP9.5 表达减少，apocynin 治疗可改善这种减少。NAT、TH 和 PGP9.5 蛋白和 mRNA 表达减少，apocynin 治疗可减轻这种减少。在用 NADPH 氧化酶抑制剂二苯基碘鎓进行的另一项实验中证实了 apocynin 的作用。总之，NADPH 氧化酶抑制剂 apocynin 减轻了兔 MI 后 CHF 中增加的心肌氧化应激和心脏交感神经末梢减少。这些发现表明，NADPH 氧化酶的激活介导了 CHF 中心肌交感神经末梢的异常，抑制 NADPH 氧化酶可能有益于心力衰竭的治疗。
