This application is submitted in response to PAR-02-049, and addresses the research objective: Improving Health and Quality of Life of Older People 2: Cardiovascular and Cerebrovascular Aging. Impaired regulation of vascular tone is central to the pathogenesis of hypertension, a disease whose prevalence is greatly increased among the elderly. In post-menopausal women, hypertension is associated with reduced availability of nitric oxide (NO), an endogenous vasodilator synthesized by endothelial nitric oxide synthase (eNOS). Studies in female spontaneous hypertensive rats (SHR) indicate that NO availability is reduced by the concurrent generation of superoxide anion, produced in the endothelium by NOS. Together these studies suggest that modulation of eNOS activity is pivotal to the pathogenesis of hypertension, eNOS is palmitoylated, a modification directing it to the caveolar membrane, where it is inactivated by cav-l. Recently, we identified a long chain fatty acyl CoA synthetase that prefers palmitic acid and is highly expressed in the vascular endothelium (eLCFACoAS). Preliminary evidence shows that: 1) inhibiting LCFACoAS reduces eNOS palmitoylation; 2) changes in LCFACoAS activity are associated with reciprocal changes in tonic in vivo but not in vitro NOS activity and 3) eLCFACOAS is up-regulated in ovariectomized rats, a model for diminished eNOS function in post-menopausal females. These data suggest the hypothesis that, by reducing eNOS funcition, eLCFACoAS contributes to the hypertension associated with age-related estrogen loss.. Our hypothesis will be tested by addressing these specific aims. First, we will quantify the role of eLCFACoAS in the regulation of eNOS function and vascular tone in aortic rings from intact and ovariectomized SHR rats. We predict that inhibiting the LCFACoAS activity will decrease reactivity to vasoconstrictor substances. Second, we will quantify eLCFACoAS activity in heart and vascular tissue of these same rats. We predict that eLCFACoAS will be greater in the ovariectomized vs intact rats and greater in the SHR vs WKY normotensive controls. If our hypothesis is correct, then eLCFACoAS might represent a new and novel target for rational drug desian in the treatment of hvpertension.
| Weis, Margaret T; Brady, Monica; Moore, Mike et al. (2005) Inhibiting long-chain fatty acyl CoA synthetase does not increase agonist-induced release of arachidonate metabolites from human endothelial cells. J Vasc Res 42:275-83 |
| Weis, Margaret T; Crumley, Jason L; Young, Lindon H et al. (2004) Inhibiting long chain fatty Acyl CoA synthetase increases basal and agonist-stimulated NO synthesis in endothelium. Cardiovasc Res 63:338-46 |
