Heart failure is an increasingly prevalent disease syndrome with a poor long-term prognosis. As a result of progressive myocardial dysfunction, the adrenergic nervous system and the renin-angiotensin system are abnormally activated. One consequence of persistently elevated adrenergic drive is the activation of multiple compensatory physiological and cellular mechanisms resulting in the down-regulation and desensitization of the myocardial beta-adrenergic receptor (AR) pathways. To investigate the mechanisms involved in beta-AR down-regulation, we and others, have found that steady-state abundance beta-AR mRNA is a critical factor in overall gene expression. Further, it is clear that both transcriptional and post-transcription regulatory mechanisms are important contributors. Although mechanisms responsible for regulation of adrenergic receptor mRNAs have not been investigated extensively, it is becoming increasingly clear that analogous to protooncogenes and cytokines, up- and down-regulation of G-protein-coupled receptor mRNAs by stabilization/destabilization of the mRNA is an important regulatory paradigm. To date, subtype- and species-dependent agonist-mediated destabilization of beta-AR mRNAs has been described by us and by others. We, and others, have go on to define cis-acting sequences, primarily in the 3'UTR, important for modulating rnRNA stability. Where we have taken a leading role is in the description of trans-acting factors such as AUF1, and HuR, that bind to specific Arich regions of beta-AR mRNAs and putatively act to stabilize of destabilize the mRNA. The essence of this proposal is to continue to explore, in depth, the effect of specific trans-acting factors on both stabilization and destabilization of beta-AR mRNA. The results of these studies should extend our knowledge in several important areas. But, first and foremost, these studies should help us understanding in greater detail, a major regulatory mechanism of gene expression relevant to not just proto-oncogenes and cytokines, but to a wide variety of genes important to cardiovascular function.

R01HL051239

1994-01-01

2010-06-30