NOX2 amplifies acetaldehyde-mediated cardiomyocyte mitochondrial dysfunction in alcoholic cardiomyopathy.
Alcoholic cardiomyopathy (ACM) resulting from excess alcohol consumption is an important cause of heart failure (HF). Although it is assumed that the cardiotoxicity of the ethanol (EtOH)-metabolite acetaldehyde (ACA) is central for its development and progression, the exact mechanisms remain obscure. Murine cardiomyocytes (CMs) exposed to ACA or EtOH showed increased superoxide (O2(•-)) levels and decreased mitochondrial polarization, both being normalized by NADPH oxidase (NOX) inhibition. C57BL/6 mice and mice deficient for the ACA-degrading enzyme mitochondrial aldehyde dehydrogenase (ALDH-2(-/-)) were fed a 2% EtOH diet for 5 weeks creating an ACA-overload. 2% EtOH-fed ALDH-2(-/-) mice exhibited a decreased cardiac function, increased heart-to-body and lung-to-body weight ratios, increased cardiac levels of the lipid peroxidation product malondialdehyde (MDA) as well as increased NOX activity and NOX2/glycoprotein 91(phox) (NOX2/gp91(phox)) subunit expression compared to 2% EtOH-fed C57BL/6 mice. Echocardiography revealed that ALDH-2(-/-)/gp91(phox-/-) mice were protected from ACA-overload-induced HF after 5 weeks of 2% EtOH-diet, demonstrating that NOX2-derived O2(•-) contributes to the development of ACM. Translated to human pathophysiology, we found increased gp91(phox) expression in endomyocardial biopsies of ACM patients. In conclusion, ACM is promoted by ACA-driven mitochondrial dysfunction and can be improved by ablation of NOX2/gp91(phox). NOX2/gp91(phox) therefore might be a potential pharmacological target to treat ACM.
Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.|Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Moritz
M
Brandt
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Venkata
V
Garlapati
Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Matthias
M
Oelze
Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Efthymios
E
Sotiriou
Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.|Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Maike
M
Knorr
Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Swenja
S
Kröller-Schön
Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Sabine
S
Kossmann
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Tanja
T
Schönfelder
Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
Henning
H
Morawietz
Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.|German Center for Cardiovascular Research (DZHK), partner site Rhine Main, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Eberhard
E
Schulz
Institut für kardiale Diagnostik und Therapie, Moltkestrasse 31, 12203 Berlin, Germany.
Heinz-Peter
HP
Schultheiss
Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.|German Center for Cardiovascular Research (DZHK), partner site Rhine Main, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Andreas
A
Daiber
Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.|Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.|German Center for Cardiovascular Research (DZHK), partner site Rhine Main, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Thomas
T
Münzel
Cardiology 1, Center for Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.|Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.|German Center for Cardiovascular Research (DZHK), partner site Rhine Main, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Philip
P
Wenzel
D000079:Acetaldehyde / Q000633:toxicity; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics; D000818:Animals; D002310:Cardiomyopathy, Alcoholic / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D000074662:NADPH Oxidase 2 / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D017382:Reactive Oxygen Species; D013481:Superoxides; D000431:Ethanol; C515029:ALDH2 protein, mouse; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000079:Acetaldehyde