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/or desensitization of the myocardial beta-adrenergic receptor (AR) pathways. We and others, have found that in both failing heart and in cells exposed to beta-agonist, the degree of down-regulation of beta-AR mRNA and protein correlate closely. Thus, regulation of beta-AR mRNA steady-state abundance appears to be a critical regulator factor dictating overall expression of this gene. Further, it is clear that both transcriptional and post-transcription mechanisms are involved in regulating beta-AR mRNA abundance. In this proposal, we focus on post-transcriptional mechanisms. Although many of the details of post-transcriptional mechanisms responsible for regulation of beta-AR mRNAs have not been elucidated, it is apparent that analogous to proto-oncogenes and cytokines, up- and down-regulation of G-protein-coupled receptor mRNAs by stabilization/destabilization of the mRNA may be an important regulatory paradigm. We, and others, have defined cis- acting sequences (AU-rich regions), primarily within the 3'UTRs of beta-ARs, that are important for modulating mRNA stability. The direction that we are now pursuing involves the description and characterization of several trans-acting factors (mRNA binding proteins) that bind specifically and with high-affinity to AU-rich regions of beta-AR mRNAs and in doing so, are hypothesized to either stabilize or destabilize the transcript. The essence of this proposal is to begin to explore at a mechanistic level the properties and mechanisms by which specific trans-acting factors either directly or indirectly stabilize or destabilize beta-AR mRNAs. These studies should help us to understand in considerably greater detail, a major regulatory mechanism of gene expression relevant to not just proto-oncogenes and cytokines, but to a wide variety of genes, including G-protein-coupled receptors, that are important to cardiovascular function.
| Port, J David; Walker, Lori A; Polk, Jeremy et al. (2011) Temporal expression of miRNAs and mRNAs in a mouse model of myocardial infarction. Physiol Genomics 43:1087-95 |
| Dockstader, Karen; Nunley, Karin; Karimpour-Fard, Anis et al. (2011) Temporal analysis of mRNA and miRNA expression in transgenic mice overexpressing Arg- and Gly389 polymorphic variants of the ?1-adrenergic receptor. Physiol Genomics 43:1294-306 |
| Port, J David; Bristow, Michael R (2011) Aptamer therapy for heart failure? Circ Res 109:982-3 |
| David Gerecht, Pamela S; Taylor, Molly A; Port, J David (2010) Intracellular localization and interaction of mRNA binding proteins as detected by FRET. BMC Cell Biol 11:69 |
| Port, J David; Sucharov, Carmen (2010) Role of microRNAs in cardiovascular disease: therapeutic challenges and potentials. J Cardiovasc Pharmacol 56:444-53 |
| Sucharov, Carmen; Bristow, Michael R; Port, J David (2008) miRNA expression in the failing human heart: functional correlates. J Mol Cell Cardiol 45:185-92 |
