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The role of the RNA binding proteins HuR and AUF1 in β1‐adrenergic receptor mRNA stability in heart failure (652.13)
Author(s) -
Kraynik Stephen,
Anthony Sarah,
Kelley Melissa,
Tranter Michael
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.652.13
Subject(s) - heart failure , contractility , messenger rna , cardiac function curve , gene silencing , pressure overload , agonist , receptor , medicine , microbiology and biotechnology , endocrinology , biology , chemistry , biochemistry , cardiac hypertrophy , gene
Cardiovascular disease is the leading cause of death in the United States. It is known that heart failure is marked by a decrease in expression of key proteins that regulate cardiac contractility, including the β 1 ‐adrenergic receptor (β 1 ‐AR). Despite a compensatory increase in sympathetic tone, cardiac contractility and inotropic response are substantially impaired, primarily through β 1 ‐AR desensitization and mRNA degradation. Here we aim to elucidate the mechanisms by which the β 1 ‐AR is regulated via mRNA processing at the regulatory 3’‐end (alternative polyadenylation), and identify the role that RNA binding proteins, such as HuR and AUF‐1, play in β 1 ‐AR mRNA stability. We demonstrate a decrease in β 1 ‐AR mRNA in cardiac pathology models of pressure overload induced heart failure (transverse aortic constriction; TAC) and chronic (2 week) β AR stimulation. In addition, we show the effect that cardiac‐specific deletion of HuR has on heart function and β 1 ‐AR mRNA regulation. We also investigate the mechanisms of agonist‐dependent β 1 ‐AR mRNA degradation in murine embryonic fibroblasts treated with β 1 ‐AR agonists and antagonists with overexpression and/or siRNA‐mediated silencing of HuR and AUF1. These findings provide important insight into the regulation of the β 1 ‐AR in heart failure and may suggest new therapeutic targets for the restoration of healthy adrenergic function.