Frontiers in Pharmacology (Mar 2023)
ALDH2 attenuates myocardial pyroptosis through breaking down Mitochondrion-NLRP3 inflammasome pathway in septic shock
- Ying Zhang,
- Ying Zhang,
- Ying Zhang,
- Ying Zhang,
- Ying Lv,
- Ying Lv,
- Ying Lv,
- Ying Lv,
- Qingju Zhang,
- Qingju Zhang,
- Qingju Zhang,
- Qingju Zhang,
- Xingfang Wang,
- Xingfang Wang,
- Xingfang Wang,
- Xingfang Wang,
- Qi Han,
- Qi Han,
- Qi Han,
- Qi Han,
- Yan Liang,
- Yan Liang,
- Yan Liang,
- Yan Liang,
- Simeng He,
- Simeng He,
- Simeng He,
- Simeng He,
- Qiuhuan Yuan,
- Qiuhuan Yuan,
- Qiuhuan Yuan,
- Qiuhuan Yuan,
- Jiaqi Zheng,
- Jiaqi Zheng,
- Jiaqi Zheng,
- Jiaqi Zheng,
- Changchang Xu,
- Changchang Xu,
- Changchang Xu,
- Changchang Xu,
- Xiangxin Zhang,
- Xiangxin Zhang,
- Xiangxin Zhang,
- Xiangxin Zhang,
- Zichen Wang,
- Zichen Wang,
- Zichen Wang,
- Zichen Wang,
- Huaxiang Yu,
- Huaxiang Yu,
- Huaxiang Yu,
- Huaxiang Yu,
- Li Xue,
- Li Xue,
- Li Xue,
- Li Xue,
- Jiali Wang,
- Jiali Wang,
- Jiali Wang,
- Jiali Wang,
- Feng Xu,
- Feng Xu,
- Feng Xu,
- Feng Xu,
- Jiaojiao Pang,
- Jiaojiao Pang,
- Jiaojiao Pang,
- Jiaojiao Pang,
- Yuguo Chen,
- Yuguo Chen,
- Yuguo Chen,
- Yuguo Chen
Affiliations
- Ying Zhang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Ying Zhang
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Ying Zhang
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Ying Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Ying Lv
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Ying Lv
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Ying Lv
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Ying Lv
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Qingju Zhang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Qingju Zhang
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Qingju Zhang
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Qingju Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Xingfang Wang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Xingfang Wang
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Xingfang Wang
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Xingfang Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Qi Han
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Qi Han
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Qi Han
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Qi Han
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Yan Liang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Yan Liang
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Yan Liang
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Yan Liang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Simeng He
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Simeng He
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Simeng He
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Simeng He
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Qiuhuan Yuan
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Qiuhuan Yuan
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Qiuhuan Yuan
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Qiuhuan Yuan
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Jiaqi Zheng
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Jiaqi Zheng
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Jiaqi Zheng
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Jiaqi Zheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Changchang Xu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Changchang Xu
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Changchang Xu
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Changchang Xu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Xiangxin Zhang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Xiangxin Zhang
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Xiangxin Zhang
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Xiangxin Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Zichen Wang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Zichen Wang
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Zichen Wang
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Zichen Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Huaxiang Yu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Huaxiang Yu
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Huaxiang Yu
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Huaxiang Yu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Li Xue
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Li Xue
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Li Xue
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Li Xue
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Jiali Wang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Jiali Wang
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Jiali Wang
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Jiali Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Feng Xu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Feng Xu
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Feng Xu
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Feng Xu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Jiaojiao Pang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Jiaojiao Pang
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Jiaojiao Pang
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Jiaojiao Pang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- Yuguo Chen
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Yuguo Chen
- Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China
- Yuguo Chen
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- Yuguo Chen
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
- DOI
- https://doi.org/10.3389/fphar.2023.1125866
- Journal volume & issue
-
Vol. 14
Abstract
Cell survival or death is critical for cardiac function. Myocardial pyroptosis, as a newly recognized programmed cell death, remains poorly understood in sepsis. In this study, we evaluated the effect of aldehyde dehydrogenase (ALDH2) on myocardial pyroptosis and revealed the underlying mechanisms in sepsis. We established a septic shock mice model by intraperitoneal injection of Lipopolysaccharide (LPS, 15 mg/kg) 12 h before sacrifice. It was found that aldehyde dehydrogenase significantly inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation and Caspase-1/GSDMD-dependent pyroptosis, which remarkably improved survival rate and septic shock-induced cardiac dysfunction, relative to the control group. While aldehyde dehydrogenase knockout or knockdown significantly aggravated these phenomena. Intriguingly, we found that aldehyde dehydrogenase inhibited LPS-induced deacetylation of Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex α subunit (HADHA) by suppressing the translocation of Histone deacetylase 3 (HDAC3) from nuclei to mitochondria. Acetylated HADHA is essential for mitochondrial fatty acid β-oxidation, and its interruption can result in accumulation of toxic lipids, induce mROS and cause mtDNA and ox-mtDNA release. Our results confirmed the role of Histone deacetylase 3 and HADHA in NOD-like receptor protein 3 inflammasome activation. Hdac3 knockdown remarkedly suppressed NOD-like receptor protein 3 inflammasome and pyroptosis, but Hadha knockdown eliminated the effect. aldehyde dehydrogenase inhibited the translocation of Histone deacetylase 3, protected ac-HADHA from deacetylation, and significantly reduced the accumulation of toxic aldehyde, and inhibited mROS and ox-mtDNA, thereby avoided NOD-like receptor protein 3 inflammasome activation and pyroptosis. This study provided a novel mechanism of myocardial pyroptosis through mitochondrial Histone deacetylase 3/HADHA- NOD-like receptor protein 3 inflammasome pathway and demonstrated a significant role of aldehyde dehydrogenase as a therapeutic target for myocardial pyroptosis in sepsis.
Keywords
