NOX2 amplifies acetaldehyde-mediated cardiomyocyte mitochondrial dysfunction in alcoholic cardiomyopathy.
Title | NOX2 amplifies acetaldehyde-mediated cardiomyocyte mitochondrial dysfunction in alcoholic cardiomyopathy. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Brandt, M., Garlapati V., Oelze M., Sotiriou E., Knorr M., Kröller-Schön S., Kossmann S., Schönfelder T., Morawietz H., Schulz E., Schultheiss H-P., Daiber A., Münzel T., & Wenzel P. |
Journal | Sci Rep |
Volume | 6 |
Pagination | 32554 |
Date Published | 2016 09 14 |
ISSN | 2045-2322 |
Keywords | Acetaldehyde, Aldehyde Dehydrogenase, Mitochondrial, Animals, Cardiomyopathy, Alcoholic, Disease Models, Animal, Ethanol, Gene Expression Regulation, Heart Failure, Humans, Mice, Mitochondria, Myocytes, Cardiac, NADPH Oxidase 2, Reactive Oxygen Species, Superoxides |
Abstract | 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. |
DOI | 10.1038/srep32554 |
Alternate Journal | Sci Rep |
PubMed ID | 27624556 |
PubMed Central ID | PMC5021994 |