The regulation of blood pressure and volume is critically dependent on a number of hormones including ANF (atrial natriuretic factor) and BNP (brain natriuretic peptide). ANF and BNP are structurally related cardiac-derived peptides that decrease intravascular volume and arterial pressure. Sustained increases in blood pressure often elicit the synthesis and release of the peptides from the heart as part of a compensatory endocrine response. To better understand blood pressure and volume regulation, as well as the underlying causes of hypertension, it is the broad objective of our research program to elucidate the mechanisms governing the production of ANF and BNP. The specific objective of this proposal is to elucidate the post-transcriptional mechanisms responsible for regulating cardiac natriuretic peptide expression, focusing on how pressor hormones can augment the half-life of the BNP transcript.
The Specific Aims are to: 1) evaluate the differential effects of pressor compounds (natriuretic peptide inducers) on the stabilities of the BNP and ANF mRNAs in primary neonatal rat myocardial cells 2) identify elements in the BNP and ANF transcripts that influence mRNA half-life 3) characterize the factor(s) that bind to these elements and to determine if inducers alter binding in a manner consistent with involvement of these factors in BNP mRNA stabilization 4) study the signaling mechanisms by which pressor compounds stabilize the BNP mRNA The proposed studies will be the first to investigate the hormonal regulation of transcript stability in cardiac myocytes. Accordingly we expect to produce novel results relating not just to natriuretic peptide expression, but to cardiac gene expression in general. Moreover, the planned studies of the signal transduction pathways by which inducers augment BNP mRNA stability will produce new results pertaining to agonist- regulated transcript half-life in cardiac myocytes as well as other cell types.
