Published online before print January 26, 2006, doi: 10.1161/01.RES.0000204825.66410.0b
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Submitted on August 26, 2005
Revised on December 28, 2005
Accepted on January 12, 2006
Elevated Homocysteine Reduces Apolipoprotein A-I Expression in Hyperhomocysteinemic Mice and in Males With Coronary Artery Disease
Leonie G. Mikael ;
From the Departments of Human Genetics and Pediatrics (L.G.M., R.R.), Montreal Children’s Hospital; and The Department of Medicine (J.G.), Royal Victoria Hospital, McGill University Health Center, Montreal, Canada.
* To whom correspondence should be addressed. E-mail: rima.rozen{at}mcgill.ca.
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 7
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<0.01) negative correlation (-0.33) between ApoA-I and plasma homocysteine levels. This cohort also displayed a negative correlation (-0.24, P=0.06) between high-density lipoprotein cholesterol and plasma homocysteine. Treatment of HepG2 cells with supraphysiological levels of 5 mmol/L homocysteine reduced peroxisome proliferator-activated receptor (PPAR) and ApoA-I protein levels and decreased ApoA-I promoter activity. Transfection with a PPAR construct upregulated ApoA-I and MTHFR. Our results suggest that hyperhomocysteinemia may increase risk of atherosclerosis by decreasing expression of ApoA-I and increasing expression of CYP7A1.
Key words: homocysteine • methylenetetrahydrofolate reductase • apolipoprotein A-I • high-density lipoprotein • peroxisome proliferator-activated receptor
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