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Mitochondrial ALDH2 protects against lipopolysaccharide-induced myocardial contractile dysfunction by suppression of ER stress and autophagy.
Pang, Jiaojiao; Peng, Hu; Wang, Shuyi; Xu, Xihui; Xu, Feng; Wang, Qiurong; Chen, Yuanzhuo; Barton, Linzi A; Chen, Yuguo; Zhang, Yingmei; Ren, Jun.
Afiliação
  • Pang J; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Emergency Medicine and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
  • Peng H; Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China.
  • Wang S; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
  • Xu X; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
  • Xu F; Department of Emergency Medicine and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
  • Wang Q; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
  • Chen Y; Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China.
  • Barton LA; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
  • Chen Y; Department of Emergency Medicine and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China. Electronic address: chen919085@126.com.
  • Zhang Y; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Fudan University Zhongshan Hospital, Shanghai 200032, China. Electronic address: zhangym1979
  • Ren J; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Fudan University Zhongshan Hospital, Shanghai 200032, China. Electronic address: jren@uwyo.e
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1627-1641, 2019 06 01.
Article em En | MEDLINE | ID: mdl-30946956
Lipopolysaccharide (LPS), an essential component of outer membrane of the Gram-negative bacteria, plays a pivotal role in myocardial anomalies in sepsis. Recent evidence depicted an essential role for mitochondrial aldehyde dehydrogenase (ALDH2) in cardiac homeostasis. This study examined the effect of ALDH2 on endotoxemia-induced cardiac anomalies. Echocardiographic, cardiac contractile and intracellular Ca2+ properties were examined. Our results indicated that LPS impaired cardiac contractile function (reduced fractional shortening, LV end systolic diameter, peak shortening, maximal velocity of shortening/relengthening, prolonged relengthening duration, oxidation of SERCA, and intracellular Ca2+ mishandling), associated with ER stress, inflammation, O2- production, increased autophagy, CAMKKß, phosphorylated AMPK and suppressed phosphorylation of mTOR, the effects of which were significantly attenuated or negated by ALDH2. LPS promoted early endosomal formation (as evidenced by RAB4 and RAB5a), apoptosis and necrosis (MTT and LDH) while decreasing late endosomal formation (RAB7 and RAB 9), the effects were reversed by ALDH2. In vitro study revealed that LPS-induced SERCA oxidation, autophagy and cardiac dysfunction were abrogated by ALDH2 activator Alda-1, the ER chaperone TUDCA, the autophagy inhibitor 3-MA, or the AMPK inhibitor Compound C. The beneficial effect of Alda-1 against LPS was nullified by AMPK activator AICAR or rapamycin. CAMKKß inhibition failed to rescue LPS-induced ER stress. Tunicamycin-induced cardiomyocyte dysfunction was ameliorated by Alda-1 and autophagy inhibition, the effect of which was abolished by rapamycin. These data suggested that ALDH2 protected against LPS-induced cardiac anomalies via suppression of ER stress, autophagy in a CAMKKß/AMPK/mTOR-dependent manner.
Assuntos
Aldeído-Desidrogenase Mitocondrial/genética; Cálcio/metabolismo; Cardiomiopatias/genética; Lipopolissacarídeos/farmacologia; Mitocôndrias/efeitos dos fármacos; Miócitos Cardíacos/efeitos dos fármacos; Proteínas Quinases Ativadas por AMP/antagonistas & inibidores; Proteínas Quinases Ativadas por AMP/genética; Proteínas Quinases Ativadas por AMP/metabolismo; Adenina/análogos & derivados; Adenina/farmacologia; Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores; Aldeído-Desidrogenase Mitocondrial/metabolismo; Animais; Autofagia/efeitos dos fármacos; Autofagia/genética; Benzamidas/farmacologia; Benzodioxóis/farmacologia; Sinalização do Cálcio; Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores; Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética; Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo; Cardiomiopatias/induzido quimicamente; Cardiomiopatias/enzimologia; Cardiomiopatias/patologia; Estresse do Retículo Endoplasmático/efeitos dos fármacos; Regulação da Expressão Gênica; Masculino; Camundongos; Camundongos Transgênicos; Mitocôndrias/enzimologia; Mitocôndrias/patologia; Contração Miocárdica/efeitos dos fármacos; Contração Miocárdica/genética; Miocárdio/enzimologia; Miocárdio/patologia; Miócitos Cardíacos/enzimologia; Miócitos Cardíacos/patologia; Cultura Primária de Células; ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética; ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo; Serina-Treonina Quinases TOR/genética; Serina-Treonina Quinases TOR/metabolismo; Ácido Tauroquenodesoxicólico/farmacologia; Proteínas rab de Ligação ao GTP/genética; Proteínas rab de Ligação ao GTP/metabolismo; Proteínas rab4 de Ligação ao GTP/genética; Proteínas rab4 de Ligação ao GTP/metabolismo; proteínas de unión al GTP Rab7
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Lipopolissacarídeos / Cálcio / Miócitos Cardíacos / Aldeído-Desidrogenase Mitocondrial / Mitocôndrias / Cardiomiopatias Idioma: En Revista: Biochim Biophys Acta Mol Basis Dis Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Lipopolissacarídeos / Cálcio / Miócitos Cardíacos / Aldeído-Desidrogenase Mitocondrial / Mitocôndrias / Cardiomiopatias Idioma: En Revista: Biochim Biophys Acta Mol Basis Dis Ano de publicação: 2019 Tipo de documento: Article