iNOS contributes to heart failure with preserved ejection fraction through mitochondrial dysfunction and Akt S-nitrosylation

作者全名："Guo, Yongzheng; Wen, Junjie; He, An; Qu, Can; Peng, Yuce; Luo, Suxin; Wang, Xiaowen"

作者地址："[Guo, Yongzheng; He, An; Peng, Yuce; Luo, Suxin] Chongqing Med Univ, Div Cardiol, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Wen, Junjie] Sichan Univ, Div Cardiol, West China Guangan Hosp, Guangan 638500, Peoples R China; [Qu, Can] Chongqing Med Univ, Dept Pharm, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Wang, Xiaowen] Chongqing Med Univ, Dept Cardiothorac Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China"

通信作者："Luo, SX (通讯作者)，Chongqing Med Univ, Div Cardiol, Affiliated Hosp 1, Chongqing 400016, Peoples R China.; Wang, XW (通讯作者)，Chongqing Med Univ, Dept Cardiothorac Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China."

来源：JOURNAL OF ADVANCED RESEARCH

ESI学科分类：Multidisciplinary

WOS号：WOS:000916473500001

JCR分区：Q1

影响因子：10.7

年份：2023

卷号：43

期号：　

开始页：175

结束页：186

文献类型：Article

关键词：HFpEF; iNOS; Akt S-nitrosylation; Mitochondrial function

摘要："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 Nx-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 inhibi-tion, 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 pathophysiolog-ical development of HFpEF, indicating that iNOS inhibition may represent a potential therapeutic strategy for HFpEF.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)."

基金机构："National Natural Science foundation of China [81270210, 82070238]; First Affiliated Hospital of Chongqing Medical university [PYJJ2021-05]; High-quality Development Fund of West China Guangan Hospital of Sichuan University [21FZ009]"

基金资助正文："This work was supported by the National Natural Science foun-dation of China grants (81270210, 82070238) , Cultivating fund of The First Affiliated Hospital of Chongqing Medical university (PYJJ2021-05) and High-quality Development Fund of West China Guang?an Hospital of Sichuan University (21FZ009) ."