iNOS aggravates pressure overload-induced cardiac dysfunction via activation of the cytosolic-mtDNA-mediated cGAS-STING pathway

作者全名："Guo, Yongzheng; You, Yuehua; Shang, Fei-Fei; Wang, Xiaowen; Huang, Bi; Zhao, Boying; Lv, Dingyi; Yang, Shenglan; Xie, Ming; Kong, Lingwen; Du, Dingyuan; Luo, Suxin; Tian, Xin; Xia, Yong"

作者地址："[Guo, Yongzheng; You, Yuehua; Huang, Bi; Lv, Dingyi; Yang, Shenglan; Luo, Suxin; Xia, Yong] Chongqing Med Univ, Affiliated Hosp 1, Div Cardiol, Chongqing 400016, Peoples R China; [Shang, Fei-Fei; Xia, Yong] Chongqing Med Univ, Insitute Life Sci, Chongqing 400016, Peoples R China; [Wang, Xiaowen] Chongqing Med Univ, Affiliated Hosp 1, Dept Cardiothorac Surg, Chongqing 400016, Peoples R China; [Zhao, Boying; Xie, Ming; Kong, Lingwen; Du, Dingyuan] Chongqing Univ Cent Hosp, Dept Cardiothorac Surg, Chongqing 400014, Peoples R China; [Tian, Xin] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing Key Lab Neurol, Chongqing 400016, Peoples R China; [Xia, Yong] Ohio State Univ, Dais Heart & Lung Res Inst, Div Cardiovasc Med, Coll Med, Columbus, OH 43210 USA; [Xia, Yong] Ohio State Univ, Div Cardiovasc Med, Med & Biochem, Coll Med, Columbus, OH 43210 USA; [Luo, Suxin] Chongqing Med Univ, Affiliated Hosp 1, Div Cardiol, Chongqing Key Lab Neurol, Chongqing 400016, Peoples R China"

通信作者："Tian, X (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing Key Lab Neurol, Chongqing 400016, Peoples R China.; Xia, Y (通讯作者)，Ohio State Univ, Div Cardiovasc Med, Med & Biochem, Coll Med, Columbus, OH 43210 USA.; Luo, SX (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Div Cardiol, Chongqing Key Lab Neurol, Chongqing 400016, Peoples R China."

来源：THERANOSTICS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001042558200021

JCR分区：Q1

影响因子：12.4

年份：2023

卷号：13

期号：12

开始页：4229

结束页：4246

文献类型：Article

关键词：mtDNA; cGAS; iNOS; Sterile inflammation; Cardiac dysfunction

摘要："Background: Sterile inflammation contributes to the pathogenesis of cardiac dysfunction caused by various conditions including pressure overload in hypertension. Mitochondrial DNA (mtDNA) released from damaged mitochondria has been implicated in cardiac inflammation. However, the upstream mechanisms governing mtDNA release and how mtDNA activates sterile inflammation in pressure-overloaded hearts remain largely unknown. Here, we investigated the role of inducible NO synthase (iNOS) on pressure overload-induced cytosolic accumulation of mtDNA and whether mtDNA activated inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Methods: To investigate whether the cGAS-STING cascade was involved in sterile inflammation and cardiac dysfunction upon pressure overload, cardiomyocyte-specific STING depletion mice and mice injected with adeno-associated virus-9 (AAV-9) to suppress the cGAS-STING cascade in the heart were subjected to transverse aortic constriction (TAC). iNOS null mice were used to determine the role of iNOS in cGAS-STING pathway activation in pressure-stressed hearts.Results: iNOS knockout abrogated mtDNA release and alleviated cardiac sterile inflammation resulting in improved cardiac function. Conversely, activating the cGAS-STING pathway blunted the protective effects of iNOS knockout. Moreover, iNOS activated the cGAS-STING pathway in isolated myocytes and this was prevented by depleting cytosolic mtDNA. In addition, disruption of the cGAS-STING pathway suppressed inflammatory cytokine transcription and modulated M1/M2 macrophage polarization, and thus mitigated cardiac remodeling and improved heart function. Finally, increased iNOS expression along with cytosolic mtDNA accumulation and cGAS-STING activation were also seen in human hypertensive hearts. Conclusion: Our findings demonstrate that mtDNA is released into the cytosol and triggers sterile inflammation through the cGAS-STING pathway leading to cardiac dysfunction after pressure overload. iNOS controls mtDNA release and subsequent cGAS activation in pressure-stressed hearts."

基金机构："National Program on Key Basic Research Project [2014CB5 42400]; National Natural Science foundation of China [82070238, 81170112, 81270210, 8220 0422]; China Postdoctoral Science Foundation [2022M720601]; Postdoctoral Incubation Project of The First Affiliated Hospital of Chongqing Medical University [CYYY-BSHPYXM-202204]; Natural Science foundation of Chongqing [CSTB2022NSCQ- MSX0913, CSTC2020JCYJ-MSXM1276]; Postdoctoral Natural Science foundation of Chongqing [2022CQBSHTBT003]; Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0168]; Yuzhong Science and Technology Bureau of Chongqing [20170404]"

基金资助正文："This work was supported by the National Program on Key Basic Research Project (2014CB5 42400), the National Natural Science foundation of China grants (82070238, 81170112, 81270210, 8220 0422), the China Postdoctoral Science Foundation (2022M720601), the Postdoctoral Incubation Project of The First Affiliated Hospital of Chongqing Medical University (CYYY-BSHPYXM-202204), the Natural Science foundation of Chongqing (CSTB2022NSCQ-MSX0913, CSTC2020JCYJ-MSXM1276), the Postdoctoral Natural Science foundation of Chongqing (2022CQBSHTBT003), Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0168) and a grant from Yuzhong Science and Technology Bureau of Chongqing (20170404)."