Downregulation of β-Adrenoceptors in Isoproterenol-Induced Cardiac Remodeling through HuR.
Downregulation of β-Adrenoceptors in Isoproterenol-Induced Cardiac Remodeling through HuR.
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通过 HuR 下调异丙肾上腺素诱导的心脏重塑中 β-肾上腺素能受体
DOI：
10.1371/journal.pone.0152005
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Yin Q;Yang C;Wu J;Lu H;Zheng X;Zhang Y;Lv Z;Zheng X;Li Z
β-肾上腺素能受体（β-AR）在心脏重构中起重要作用，心脏重构是各种心脏疾病的关键病理过程，并导致心力衰竭。然而，β-AR在重构心脏中的表达调控仍不清楚。本研究旨在阐明β1-和β2-AR在心脏重构中的表达调控机制。采用异丙肾上腺素（ISO）0.25mg·kg-1·d-1连续7 d皮下注射建立大鼠心脏重构模型。我们发现β1-和β2-AR在重构心脏中的表达减少。其机制可能包括抑制DNA转录和增加mRNA降解。cAMP反应元件结合蛋白（CREB）是β-AR的一种转录因子。而CREB的表达和激活在重构心脏中没有改变。此外，在重塑模型中，人抗原-R（HuR）（一种RNA结合蛋白，与β-AR mRNA的3 '非翻译区结合并促进RNA降解）增加。在体外实验中，HuR缺乏可逆转ISO诱导的β-AR mRNA表达减少。因此，本研究结果表明，HuR，而不是CREB，是负责减少β-AR表达在ISO诱导的心脏重塑。
β-adrenergic receptors (β-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 β-AR expression in remodeling hearts is still unclear. This study aims to clarify the possible mechanisms underlying the regulation of β1- and β2-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 7days. We found that the expression of β1- and β2-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 β-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 β-AR mRNA and promotes RNA degradation, was increased in the remodeling model. And in vitro, HuR deficiency reversed the reduction of β-AR mRNA induced by ISO. Therefore, the present findings indicate that HuR, but not CREB, is responsible for the reduction of β-AR expression in ISO induced cardiac remodeling.