Mitochondrial Aldehyde Dehydrogenase Activation by Alda‐1 Inhibits Atherosclerosis and Attenuates Hepatic Steatosis in Apolipoprotein E‐Knockout Mice

• Published in: Journal of the American Heart Association Vol. 3; no. 6; pp. e001329 - n/a
• Main Authors: Stachowicz, Aneta, Olszanecki, Rafał, Suski, Maciej, Wiśniewska, Anna, Totoń‐Żurańska, Justyna, Madej, Józef, Jawień, Jacek, Białas, Magdalena, Okoń, Krzysztof, Gajda, Mariusz, Głombik, Katarzyna, Basta‐Kaim, Agnieszka, Korbut, Ryszard
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 12-11-2014
• Subjects: Alda‐1; Aldehyde Dehydrogenase - genetics; Aldehyde Dehydrogenase - metabolism; Aldehyde Dehydrogenase, Mitochondrial; ALDH2; Animals; Aorta - drug effects; Aorta - enzymology; Aorta - pathology; Aortic Diseases - blood; Aortic Diseases - enzymology; Aortic Diseases - genetics; Aortic Diseases - pathology; Aortic Diseases - prevention & control; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; atherosclerosis; Atherosclerosis - blood; Atherosclerosis - enzymology; Atherosclerosis - genetics; Atherosclerosis - pathology; Atherosclerosis - prevention & control; Benzamides - pharmacology; Benzodioxoles - pharmacology; Biomarkers - blood; Disease Models, Animal; Enzyme Activation; Enzyme Activators - pharmacology; Female; Gene Expression Regulation; Hep G2 Cells; Humans; Liver - drug effects; Liver - enzymology; Liver - pathology; Mice, Inbred C57BL; Mice, Knockout; mitochondria; Mitochondria, Liver - drug effects; Mitochondria, Liver - enzymology; Non-alcoholic Fatty Liver Disease - blood; Non-alcoholic Fatty Liver Disease - enzymology; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - pathology; Non-alcoholic Fatty Liver Disease - prevention & control; nonalcoholic fatty liver disease; Original Research; Signal Transduction - drug effects; atherosclerosis; nonalcoholic fatty liver disease; ALDH2; Alda‐1; mitochondria
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.114.001329

Background
Mitochondrial dysfunction has been shown to play an important role in the development of atherosclerosis and nonalcoholic fatty liver disease (NAFLD). Mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme responsible for the detoxification of reactive aldehydes, is considered to exert protective function in mitochondria. We investigated the influence of Alda‐1, an activator of ALDH2, on atherogenesis and on the liver steatosis in apolipoprotein E knockout (apoE−/−) mice.
Methods and Results
Alda‐1 caused decrease of atherosclerotic lesions approximately 25% as estimated by “en face” and “cross‐section” methods without influence on plasma lipid profile, atherosclerosis‐related markers of inflammation, and macrophage and smooth muscle content in the plaques. Plaque nitrotyrosine was not changed upon Alda‐1 treatment, and there were no changes in aortic mRNA levels of factors involved in antioxidative defense, regulation of apoptosis, mitogenesis, and autophagy. Hematoxylin/eosin staining showed decrease of steatotic changes in liver of Alda‐1‐treated apoE−/− mice. Alda‐1 attenuated formation of 4‐hydroxy‐2‐nonenal (4‐HNE) protein adducts and decreased triglyceride content in liver tissue. Two‐dimensional electrophoresis coupled with mass spectrometry identified 20 differentially expressed mitochondrial proteins upon Alda‐1 treatment in liver of apoE−/− mice, mostly proteins related to metabolism and oxidative stress. The most up‐regulated were the proteins that participated in beta oxidation of fatty acids.
Conclusions
Collectively, Alda‐1 inhibited atherosclerosis and attenuated NAFLD in apoE−/− mice. The pattern of changes suggests a beneficial effect of Alda‐1 in NAFLD; however, the exact liver functional consequences of the revealed alterations as well as the mechanism(s) of antiatherosclerotic Alda‐1 action require further investigation.