Downregulation of ß-Adrenoceptors in Isoproterenol-Induced Cardiac Remodeling through HuR.

ß-adrenergic receptors (ß-ARs) play an important role in cardiac remodeling, which is the key pathological process in various heart diseases and leads to heart failure. However, the regulation of ß-AR expression in remodeling hearts is still unclear. This study aims to clarify the possible mechanisms underlying the regulation of ß1- and ß2-AR expression in cardiac remodeling. The rat model of cardiac remodeling was established by subcutaneous injection of isoproterenol(ISO) at the dose of 0.25 mg·kg(-1)·d(-1) for 7 days. We found that the expression of ß1- and ß2-ARs decreased in the remodeling heart. The mechanisms may include the inhibition of DNA transcription and the increase of mRNA degradation. cAMP-response element binding protein(CREB) is a well-known transcription factor of ß-AR. However, the expression and activation of CREB was not changed in the remodeling heart. Further, human Antigen-R (HuR), a RNA binding protein, which binds to the 3'-untranslated region of the ß-AR mRNA and promotes RNA degradation, was increased in the remodeling model. And in vitro, HuR deficiency reversed the reduction of ß-AR mRNA induced by ISO. Therefore, the present findings indicate that HuR, but not CREB, is responsible for the reduction of ß-AR expression in ISO induced cardiac remodeling.