Grant: Operating Grant

Hypertension is a multigenic disease that leads to cardiac hypertrophy (enlargement of the heart) and cardiac failure. We have recently shown that the genes for Gia proteins (Gia-2 and Gialp-3) that decrease the levels of cyclic AMP and increase blood pressure (BP),were overexpressed in genetic (SHR) and experimental models of hypertensive rats (HR). However, the contribution of Gia-2 or Gia-3 or both in the pathogenesis of hypertension is not clear. Therefore, we will examine the effect of deletion of Gia-2 and Gia-3 proteins by using antisense approach on the development of BP in SHR. To further establish the implication of enhanced expression of Gia proteins in hypertension, we will use SNAP and sodium nitroprusside (SNP), nitric oxide(NO) donors and vasorelaxants , that attenuate the increased expression of Gia proteins in SHR to examine if these agents could also decrease the BP in HR. We have earlier shown the contribution of enhanced oxidative stress in the augmented expression of Gia proteins in SHR, we will extend our studies to examine the effect of antioxidants on the development of BP and their relationship with Gia protein expression. Since hypertension leads to cardiac hypertrophy and the contribution of vascular Gq protein-coupled signaling in the development of cardiac hypertrophy has been shown, we will investigate if the expression of Gq is augmented in VSMC from different rat models exhibiting hypertension with or without cardiac hypertrophy and cardiac hypertrophy without hypertension and its relationship with vascular hypertrophy. Finally, we will also examine the molecular mechanisms contributing to the enhanced expression of G proteins in hypertension and hypertrophy and by which the antioxidants and NO donors attenuate G protein expression,BP and vascular hypertrophy. It is hoped that the results from this work will eventually form the basis for developing new therapeutic interventions for the management of hypertension and hypertrophy