The long range objectives of these studies is to determine the relationship between the regulation of the cholesterol metabolic pathway and the activation of RAS in cultured heart cells, and the mechanism by which RAS controls the expression of genes coding for receptors, G-proteins, and effectors which mediate the autonomic response of the heart. The applicant proposes to test the hypothesis that farnesyl-protein transferase (FPTase), the enzyme which catalyzes the farnesylation of RAS, is a regulatable enzyme under the feedback control of LDL cholesterol and that induction of FPTase increases the level of membrane-associated RAS. The applicant will also test the hypothesis that an increase in RAS activity regulates a program of gene expression which coordinately increases levels of mRNA coding for M2 muscarinic receptors, ai2, and GIRK1 and reciprocally decreases levels of mRNA coding for beta1-adrenergic receptor, as and the Type V and Type VI adenylate cyclase. Using retroviral vectors to express an activated RAS mutant in chick heart cultures, or ventricular cultures from transgenic mice expressing an activated RAS, the applicant will test the hypothesis that activated RAS may enhance the response of atrial cells to muscarinic stimulation and induce the coupling of muscarinic receptors to GIRK1 in the ventricle. Finally, the applicant will characterize cis-acting elements in the 5' flanking region of chick ai2 responsible for the increased expression of ai2 mRNA during induction of the cholesterol metabolic pathway and in response to increased RAS activity.
|Park, Ho-Jin; Begley, Ulrike; Kong, Dequan et al. (2002) Role of sterol regulatory element binding proteins in the regulation of Galpha(i2) expression in cultured atrial cells. Circ Res 91:32-7|
|Park, H J; Galper, J B (1999) 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors up-regulate transforming growth factor-beta signaling in cultured heart cells via inhibition of geranylgeranylation of RhoA GTPase. Proc Natl Acad Sci U S A 96:11525-30|