Background: Hyperhomocysteinemia and hypoalphalipoproteinemia are two well-reported risk factors for cardiovascular disease. The effects of the synergistic combination of these two factors on vascular function need to be investigated.
Methods and results: Four groups of male mice were used: a control wild-type group; a group of mice heterozygous for cystathionine beta-synthase deficiency; a group of mice heterozygous for apolipoprotein A-I deficiency; and, finally, a group of double heterozygous mice, with both cystathionine beta-synthase and apolipoprotein A-I deficiency. To characterize the resulting phenotype, several parameters including plasma apolipoproteins, lipid profiles, homocysteine, blood pressure and aortic protein were analyzed. As expected, our results indicate that double heterozygous mice are a model of mild hypoalphalipoproteinemia and hyperhomocysteinemia. Further, the additive combination of both risk factors resulted in a significant increase in blood pressure compared with control animals (136 +/- 8.0 versus 126 +/- 7.5 mm Hg, P < 0.01) that was not present in single heterozygous mice. The increase in blood pressure was associated with decreased plasma nitric oxide levels, left ventricle hypertrophy and was independent of low-density lipoprotein (LDL) cholesterol, para-oxonase activity and kidney histological changes. Concomitant decreases in levels of apolipoprotein A-IV (APOA-IV) and caveolin-1 content were also found in the double heterozygous group.
Conclusions: Our findings suggest an additive adverse effect of hypoalphalipoproteinemia and hyperhomocysteinemia on endothelial function to generate clinical hypertension and cardiac muscle hypertrophy mediated by dysregulation in nitric oxide metabolism.