The natriuretic peptides are a family of gene products which display potent vasorelaxant and volume-contracting activity in a number of different species, including humans. Atrial natriuretic peptide (ANP) is preferentially expressed in the cardiac atria while brain natriuretic peptide (BNP) expression shows a more equivalent distribution in atrial and ventricular myocytes. Expression of both NP genes is typically suppressed in the adult ventricular myocyte but can be reactivated under pathological conditions associated with hypertrophy. In fact, expression of these genes has come to represent one of the earliest and most reliable genetic markers of hypertrophy in humans and lower animals. A number of signaling pathways (e.g. ERK, JNK, p38 MAPK, PKC, non receptor protein tyrosine kinases, etc.) have been shown to link hypertrophic stimuli (typically biochemical agonists like phenylephrine and endothelin) to various markers of hypertrophy (including NP gene expression) but the relative contributions of these individual pathways and the details of their respective signaling mechanisms in the myocyte remain only partially understood. Furthermore while agents like phenylephrine and endothelin evoke a phenotype which is reminiscent of hypertrophy in vivo, they do not reproduce the mechanical stimulation which is experienced by myocytes in a hemodynamically active environment. Finally, while activators of hypertrophy have received considerable attention, relatively little is known about endogenous factors that limit hypertrophy or hypertrophy-dependent gene expression. In the present proposal we will attempt: (1) to define the mechanism(s) underlying the suppression of NP gene promoter activity by 1,25 dihydroxyvitamin D3, (2) to determine the mechanism underlying the reduction of ANP gene promoter activity by c-Fos, (3) to expand our understanding of the role of the non-receptor protein tyrosine kinases (NRPTK's) in signaling endothelin-dependent activation of NP gene expression and (4) to investigate the mechanism(s) underlying activation of the BNP gene promoter by mechanical strain, using an in vitro model as a surrogate of hemodynamic load. Collectively these studies should provide us with a more complete picture of the molecular mechanisms which govern NP gene expression in response to hypertrophic stimuli and may suggest therapeutic interventions to control this process in clinical settings associated with hypertrophy.
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