ENDOTHELIN-3--EFFECTS ON BLOOD PRESSURE AND HEART WEIGHT

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The major interest of this laboratory is the identification and characterization of loci regulating blood pressure and cardiac hypertrophy. Our strategy is to identify these loci in rat models of genetic hypertension, focusing on the inbred Dahl rat models of blood pressure salt-sensitivity and -resistance. Endothelins are among the most potent vasoactive substrates known and also influence cell growth and the production of extracellular matrix. We have recently identified polymorphisms at the ET-3 locus distinguishing alleles in inbred Dahl salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats, We have linked the ET-3 locus to blood pressure and relative heart weight in a segregating population, derived from matings of SS.Jr rats with SR/Jr rats, that were raised on a high salt diet. The ET-3 locus was mapped to rat chromosome 3, where no loci were previously linked to blood pressure or relative heart weight. Our major goal is to identify mutations in the rat ET-3 gene that contribute to relative heart weight and blood pressure salt-sensitivity and/or salt resistance. These mutations could affect either 1) the protein-coding sequences, 2) sequences regulating mRNA transcription, or 3) sequences regulating alternative splicing of mRNA in SS/Jr and SR/Jr rats. The first possibility will be addressed by cloning and sequencing the coding region of the ET-3 alleles. The second and third possibilities will be addressed by sequence analysis of SS/Jr and SR/Jr rat ET-3 genomic clones and a Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR)-based assay. If regulatory, rather than coding, sequences appear divergent, circulating ET-3 levels and tissue ET-3 mRNBA expression will be examined in SS/Jr, SR/Jr, and congenic SS/Jr rats containing SR/Jr-rat ET-3 locus. This project will also examine the effects of genetic background on ET-3 gene expression, and the effects of this chromosome 3 locus on blood pressure and cardiac hypertrophy in inbred Dahl rats. This project will further the knowledge of ET-3 gene structure and regulation. Identifying mutations causing strain differences in ET-3 expression could help us better understand the mechanism underlying both cardiac hypertrophy and hypertension.