Elevated Homocysteine Reduces Apolipoprotein A-I Expression in Hyperhomocysteinemic Mice and in Males With Coronary Artery Disease

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional or genetic disturbances in homocysteine metabolism. A polymorphism in methylenetetrahydrofolate reductase (MTHFR) is the most common genetic cause of mild hyperhomocysteinemia. To examine mechanisms by which an...

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Bibliographic Details
Published in:Circulation research 2006-03, Vol.98 (4), p.564-571
Main Authors: Mikael, Leonie G, Genest, Jacques, Rozen, Rima
Format: Article
Language:English
Subjects:
Animals
Apolipoprotein A-I - analysis
Apolipoprotein A-I - blood
Apolipoprotein A-I - genetics
Biological and medical sciences
Cardiology. Vascular system
Cholesterol 7-alpha-Hydroxylase - genetics
Cholesterol, HDL - blood
Coronary Disease - metabolism
Coronary heart disease
Cystathionine beta-Synthase - physiology
Fundamental and applied biological sciences. Psychology
Heart
Homocystine - blood
Hyperhomocysteinemia - metabolism
Liver - metabolism
Male
Medical sciences
Methylenetetrahydrofolate Reductase (NADPH2) - deficiency
Methylenetetrahydrofolate Reductase (NADPH2) - genetics
Methylenetetrahydrofolate Reductase (NADPH2) - physiology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
PPAR alpha - physiology
Promoter Regions, Genetic
RNA, Messenger - analysis
Vertebrates: cardiovascular system
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Summary:Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional or genetic disturbances in homocysteine metabolism. A polymorphism in methylenetetrahydrofolate reductase (MTHFR) is the most common genetic cause of mild hyperhomocysteinemia. To examine mechanisms by which an elevation in plasma homocysteine leads to vascular disease, we first performed microarray analyses in livers of Mthfr-deficient mice and identified differentially expressed genes that are involved in lipid and cholesterol metabolism. Microarrays and RT-PCR showed decreased mRNA for apolipoprotein A (ApoA)-IV and for ApoA-I and increased mRNA for cholesterol 7α hydroxylase (Cyp7A1) in Mthfr mice compared with Mthfr mice. Western blotting revealed that ApoA-I protein levels in liver and plasma of Mthfr mice were 52% and 62% of levels in the respective tissues of Mthfr mice. We also performed Western analysis for plasma ApoA-I protein levels in 60 males with coronary artery disease and identified a significant (P
ISSN:0009-7330
1524-4571
DOI:10.1161/01.RES.0000204825.66410.0b