Genetically based hypertension generated through interaction of mild hypoalphalipoproteinemia and mild...

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.

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.

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.