Journal of Advanced Research ( IF 10.7 ) Pub Date : 2022-03-05 , DOI: 10.1016/j.jare.2022.03.003 Yongzheng Guo 1 , Junjie Wen 2 , An He 1 , Can Qu 3 , Yuce Peng 1 , Suxin Luo 1 , Xiaowen Wang 4
Introduction
Despite the high morbidity and mortality of heart failure with preserved fraction (HFpEF), there are currently no effective therapies for this condition. Moreover, the pathophysiological basis of HFpEF remains poorly understood.
Objective
The aim of the present study was to investigate the role of inducible nitric oxide synthase (iNOS) and its underlying mechanism in a high-fat diet and Nω-nitro-L-arginine methyl ester-induced HFpEF mouse model.
Methods
The selective iNOS inhibitor L-NIL was used to examine the effects of short-term iNOS inhibition, whereas the long-term effects of iNOS deficiency were evaluated using iNOS-null mice. Cardiac and mitochondrial function, oxidative stress and Akt S-nitrosylation were then measured.
Results
The results demonstrated that both pharmacological inhibition and iNOS knockout mitigated mitochondrial dysfunction, oxidative stress and Akt S-nitrosylation, leading to an ameliorated HFpEF phenotype in mice. In vitro, iNOS directly induced Akt S-nitrosylation at cysteine 224 residues , leading to oxidative stress, while inhibiting insulin-mediated glucose uptake in myocytes.
Conclusion
Altogether, the present findings suggested an important role for iNOS in the pathophysiological development of HFpEF, indicating that iNOS inhibition may represent a potential therapeutic strategy for HFpEF.
中文翻译:
iNOS 通过线粒体功能障碍和 Akt S-亚硝基化导致射血分数保留的心力衰竭
介绍
尽管保留分数的心力衰竭 (HFpEF) 的发病率和死亡率很高,但目前还没有针对这种情况的有效疗法。此外,HFpEF 的病理生理学基础仍然知之甚少。
客观的
本研究的目的是研究诱导型一氧化氮合酶 (iNOS) 的作用及其在高脂饮食和 N ω -硝基-L-精氨酸甲酯诱导的 HFpEF 小鼠模型中的作用。
方法
选择性 iNOS 抑制剂 L-NIL 用于检查短期 iNOS 抑制的影响,而 iNOS 缺乏的长期影响使用 iNOS 缺失小鼠进行评估。然后测量心脏和线粒体功能、氧化应激和 Akt S-亚硝基化。
结果
结果表明,药理学抑制和 iNOS 敲除均减轻了线粒体功能障碍、氧化应激和 Akt S-亚硝基化,从而改善了小鼠的 HFpEF 表型。在体外,iNOS 在半胱氨酸 224 残基处直接诱导 Akt S-亚硝基化,导致氧化应激,同时抑制肌细胞中胰岛素介导的葡萄糖摄取。
结论
总而言之,本研究结果表明 iNOS 在 HFpEF 的病理生理学发展中具有重要作用,表明 iNOS 抑制可能代表 HFpEF 的潜在治疗策略。