Systemic arterial hypertension is one of the major causes of morbidity and mortality in the U.S. , affecting more than 30 million Americans. At this time, the etiology of """"""""essential"""""""" hypertension remains unknown. The goal of the present proposal is to investigate the role of the Na/H exchanger, a ubiquitous transmembrane transport protein, in essential hypertension. Because of its role in both growth and Na regulation, the Na/H exchanger has been proposed as a logical mediator of abnormal vascular smooth muscle cell (VSMC) function in hypertension. Indeed, our laboratory has reported that VSMC from the Spontaneously Hypertensive Rat (SHR) demonstrate increased Na/H exchange activity and growth. Because we have prepared cDNAs and antibodies for the rat Na/H exchanger, it should be possible to determine the mechanisms that regulate Na/H exchange activity. We propose to define the mechanisms that regulate Na/H exchanger gene expression and function in VSMC to gain insight into the regulatory proteins that are altered in hypertension. The primary hypothesis underlying this proposal is that altered regulation of the Na/H exchanger contributes to pathophysiologic VSMC function. Published data from our laboratory show that steady state exchanger mRNA levels are markedly increased by growth factors, suggesting that it is a growth-regulated gene. To study Na/H exchanger regulation in VSMC these aims are proposed. 1: Isolate fulllength cDNA clones for the rat Na/H exchanger. 2: Determine the relative contributions of transcriptional regulatory mechanisms to the regulation of Na/H exchanger mRNA levels in growth-arrested and proliferating VSMC. 3: Determine the signal transduction mechanisms responsible for hormonal regulation of Na/H exchanger gene expression focusing on the role of protein kinase C and transforming growth factor-&. 4: Analyze the mechanisms for regulation of Na/H exchanger protein expression and function in VSMC by measurement of protein synthetic rate and phosphorylation of the exchanger. The experiments in this aim will use anti-peptide antibodies already characterized and transfection of exchange deficient VSMC mutants. 5: Compare the properties of the Na/H exchanger in VSMC from hypertensive (SHR) and normotensive (WKY) rats. The results of these studies should provide a detailed understanding of the mechanisms that regulate Na/H exchanger function in vascular smooth muscle and may provide insights into new therapeutic approaches to treat hypertension.
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