Mitochondrial aldehyde dehydrogenase activation by Alda-1 inhibits atherosclerosis and attenuates hepatic steatosis in apolipoprotein E-knockout mice.
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.


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.
Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland (A.S., R.O., M.S., A.W., J.T., M., J.J., R.K.).
Aneta
A
Stachowicz
Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland (A.S., R.O., M.S., A.W., J.T., M., J.J., R.K.).
Rafał
R
Olszanecki
Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland (A.S., R.O., M.S., A.W., J.T., M., J.J., R.K.).
Maciej
M
Suski
Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland (A.S., R.O., M.S., A.W., J.T., M., J.J., R.K.).
Anna
A
Wiśniewska
Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland (A.S., R.O., M.S., A.W., J.T., M., J.J., R.K.).
Justyna
J
Totoń-Żurańska
Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland (A.S., R.O., M.S., A.W., J.T., M., J.J., R.K.).
Józef
J
Madej
Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland (A.S., R.O., M.S., A.W., J.T., M., J.J., R.K.).
Jacek
J
Jawień
Department of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland (M.B., K.O.).
Magdalena
M
Białas
Department of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland (M.B., K.O.).
Krzysztof
K
Okoń
Department of Histology, Jagiellonian University Medical College, Krakow, Poland (M.G.).
Mariusz
M
Gajda
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland (K., A.B.K.).
Katarzyna
K
Głombik
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland (K., A.B.K.).
Agnieszka
A
Basta-Kaim
Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland (A.S., R.O., M.S., A.W., J.T., M., J.J., R.K.).
Ryszard
R
Korbut
D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001549:Benzamides / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
D001057:Apolipoproteins E; D001549:Benzamides; D052117:Benzodioxoles; D015415:Biomarkers; D020536:Enzyme Activators; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial
ALDH2; Alda‐1; atherosclerosis; mitochondria; nonalcoholic fatty liver disease