The Second Hospital of Shanxi Medical University, Taiyuan, China.
Shanxi Medical University, Taiyuan, China.
Clin Exp Pharmacol Physiol. 2021 May;48(5):704-716. doi: 10.1111/1440-1681.13465. Epub 2021 Mar 1.
Reduced nerve growth factor (NGF) is associated with cardiac sympathetic nerve denervation in heart failure (HF) which is characterized by increased oxidative stress. Apocynin is considered an antioxidant agent which inhibits NADPH oxidase activity and improves reactive oxygen species scavenging. However, it is unclear whether apocynin prevents reduced myocardial NGF, leading to improvement of cardiac function in HF. In this study, we tested the hypothesis that apocynin prevents reduced myocardial NGF, contributing to amelioration of myocardial apoptosis and failure. Rabbits with myocardial infarction (MI) or sham operation were randomly assigned to receive apocynin or placebo for 4 weeks. MI rabbits exhibited left ventricular (LV) dysfunction, and elevation in oxidative stress, as evidenced by a decreased reduced-to-oxidized glutathione ratio and an increased 4-hydroxynonenal expression, and reduction in NGF and NGF receptor tyrosine kinase A (TrKA) expression in the remote non-infarcted myocardium. Apocynin treatment ameliorated LV dysfunction, reduced oxidative stress, prevented decreases in NGF and TrKA expression and reduced cardiomyocyte apoptosis after MI. In cultured H9C2 cardiomyocytes, hypoxia or hydrogen peroxide decreased NGF expression, and apocynin normalized hypoxia-induced reduction of NGF. Recombinant NGF attenuated hypoxia-induced apoptosis. Apocynin prevented hypoxia-induced apoptosis, and the suppressive effect of apocynin on apoptosis was abolished by NGF receptor TrKA inhibitor K252a. We concluded that apocynin prevented reduced myocardial NGF, leading to attenuation of cardiomyocyte apoptosis and LV remodelling and dysfunction in HF after MI. These findings suggest that strategies to prevent NGF reduction by inhibition of oxidative stress may be of value in amelioration of LV dysfunction in HF.
神经生长因子（NGF）减少与心力衰竭（HF）中心交感神经去神经支配有关，其特征是氧化应激增加。阿朴肉桂酸被认为是一种抗氧化剂，可抑制 NADPH 氧化酶活性并改善活性氧的清除。但是，尚不清楚阿朴肉桂酸是否可以防止心肌 NGF 减少，从而改善 HF 中的心脏功能。在这项研究中，我们检验了这样一个假设，即阿朴肉桂酸可防止心肌 NGF 减少，从而改善心肌细胞凋亡和衰竭。接受心肌梗死（MI）或假手术的兔子被随机分为接受阿朴肉桂酸或安慰剂治疗 4 周。MI 兔子表现出左心室（LV）功能障碍，并伴有氧化应激升高，表现为还原型谷胱甘肽与氧化型谷胱甘肽的比例降低，4-羟壬烯醛表达增加，以及远程非梗塞心肌中 NGF 和 NGF 受体酪氨酸激酶 A（TrKA）表达减少。阿朴肉桂酸治疗可改善 LV 功能障碍，降低氧化应激，防止 MI 后 NGF 和 TrKA 表达减少并减少心肌细胞凋亡。在培养的 H9C2 心肌细胞中，缺氧或过氧化氢降低了 NGF 的表达，而阿朴肉桂酸使 NGF 诱导的降低正常化。重组 NGF 减轻了缺氧诱导的细胞凋亡。阿朴肉桂酸可预防缺氧诱导的细胞凋亡，并且 NGF 受体 TrKA 抑制剂 K252a 可消除阿朴肉桂酸对凋亡的抑制作用。我们得出结论，阿朴肉桂酸可防止心肌 NGF 减少，从而减轻 MI 后 HF 中的心肌细胞凋亡和 LV 重构及功能障碍。这些发现表明，通过抑制氧化应激来防止 NGF 减少的策略可能对改善 HF 中的 LV 功能障碍具有重要意义。
