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Mitochondrial ALDH2 protects against lipopolysaccharide-induced myocardial contractile dysfunction by suppression of ER stress and autophagy.
Biochim Biophys Acta Mol Basis Dis. 2019 06 01; 1865(6):1627-1641.BB

Abstract

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, CAMKKβ, 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. CAMKKβ 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 CAMKKβ/AMPK/mTOR-dependent manner.

Authors+Show Affiliations

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.Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China.Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.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.Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China.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. Electronic address: chen919085@126.com.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: zhangym197951@126.com.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.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30946956

Citation

Pang, Jiaojiao, et al. "Mitochondrial ALDH2 Protects Against Lipopolysaccharide-induced Myocardial Contractile Dysfunction By Suppression of ER Stress and Autophagy." Biochimica Et Biophysica Acta. Molecular Basis of Disease, vol. 1865, no. 6, 2019, pp. 1627-1641.
Pang J, Peng H, Wang S, et al. Mitochondrial ALDH2 protects against lipopolysaccharide-induced myocardial contractile dysfunction by suppression of ER stress and autophagy. Biochim Biophys Acta Mol Basis Dis. 2019;1865(6):1627-1641.
Pang, J., Peng, H., Wang, S., Xu, X., Xu, F., Wang, Q., Chen, Y., Barton, L. A., Chen, Y., Zhang, Y., & Ren, J. (2019). Mitochondrial ALDH2 protects against lipopolysaccharide-induced myocardial contractile dysfunction by suppression of ER stress and autophagy. Biochimica Et Biophysica Acta. Molecular Basis of Disease, 1865(6), 1627-1641. https://doi.org/10.1016/j.bbadis.2019.03.015
Pang J, et al. Mitochondrial ALDH2 Protects Against Lipopolysaccharide-induced Myocardial Contractile Dysfunction By Suppression of ER Stress and Autophagy. Biochim Biophys Acta Mol Basis Dis. 2019 06 1;1865(6):1627-1641. PubMed PMID: 30946956.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial ALDH2 protects against lipopolysaccharide-induced myocardial contractile dysfunction by suppression of ER stress and autophagy. AU - Pang,Jiaojiao, AU - Peng,Hu, AU - Wang,Shuyi, AU - Xu,Xihui, AU - Xu,Feng, AU - Wang,Qiurong, AU - Chen,Yuanzhuo, AU - Barton,Linzi A, AU - Chen,Yuguo, AU - Zhang,Yingmei, AU - Ren,Jun, Y1 - 2019/04/01/ PY - 2018/12/08/received PY - 2019/03/13/revised PY - 2019/03/28/accepted PY - 2019/4/5/pubmed PY - 2019/4/5/medline PY - 2019/4/5/entrez KW - ALDH2 KW - Autophagy KW - Cardiac KW - ER stress KW - Endosome KW - Lipopolysaccharide SP - 1627 EP - 1641 JF - Biochimica et biophysica acta. Molecular basis of disease JO - Biochim Biophys Acta Mol Basis Dis VL - 1865 IS - 6 N2 - 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, CAMKKβ, 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. CAMKKβ 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 CAMKKβ/AMPK/mTOR-dependent manner. SN - 1879-260X UR - https://www.unboundmedicine.com/medline/citation/30946956/Mitochondrial_ALDH2_protects_against_lipopolysaccharide_induced_myocardial_contractile_dysfunction_by_suppression_of_ER_stress_and_autophagy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(19)30109-7 DB - PRIME DP - Unbound Medicine ER -
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