OBJECTIVE The elevated expression of phospholamban (PLB) has been observed in heart failure and cardiac remodeling, inhibiting the affinity of Ca2+ pump to Ca2+ thereby impairing heart relaxation. However, the mechanisms underlying the regulation of PLB remains to be further studied. The present study aims to test the role of RNA binding protein HuR in the regulation of PLB and the impact of this regulatory process in cardiac remodeling. METHODS AND RESULTS A mouse model specifically deleted HuR in cardiomyocytes were used for testing the role of HuR in regulating PLB during isoproterenol (ISO)-induced cardiac remodeling. HuR deficiency did not significantly influence the phenotype and function of mouse heart under static status. However, deletion of HuR in cardiomyocytes mitigated the effect of ISO in inducing PLB expression and reducing β1-AR expression, in turn aggravating ISO-induced myocardial hypertrophy and cardiac fibrosis. In H9C2 cells, association of HuR with PLB and β1-AR mRNAs stabilized PLB mRNA and destabilized β1-AR mRNA, respectively. CONCLUSION HuR stabilizes PLB mRNA and destabilizes β1-AR mRNA. The HuR-PLB and HuR-β1-AR regulatory processes impact on ISO-induced cardiac remodeling. TRANSLATIONAL PERSPECTIVE PLB, the reversible inhibitor of SERCA2A, is of critical importance for the SR Ca2+ sequestration thereby the excitation-contraction coupling of myocytes and myocardial remodeling. The activity of PLB could be inhibited by β1-AR-cAMP-PKA pathway through PKA-mediated protein phosphorylation. The present study demonstrated that HuR is able to modulate cardiac remodeling by regulating the expression of PLB and β1-AR. These findings reveal novel mechanisms controlling myocardial remodeling and may provide new clues for strategies to interfere cardiac remodeling-related heart disorders in humans.

中文翻译：

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HuR调节异丙肾上腺素诱导的心脏重塑中的磷lamban表达。

目的在心力衰竭和心脏重塑中观察到磷酸lamban（PLB）的表达升高，抑制了Ca2 +泵对Ca2 +的亲和力，从而损害了心脏的舒张功能。但是，调控小脑的潜在机制有待进一步研究。本研究旨在测试RNA结合蛋白HuR在调节PLB中的作用以及该调节过程对心脏重塑的影响。方法和结果使用小鼠模型在心肌细胞中特异删除的HuR来测试HuR在异丙肾上腺素（ISO）诱导的心脏重塑期间在调节PLB中的作用。HuR缺乏并没有显着影响静态状态下小鼠心脏的表型和功能。然而，心肌细胞中HuR的缺失减轻了ISO诱导PLB表达并降低β1-AR表达的作用，从而加剧了ISO诱导的心肌肥大和心脏纤维化。在H9C2细胞中，HuR与PLB和β1-ARmRNA的结合分别使PLB mRNA稳定和β1-ARmRNA不稳定。结论HuR可稳定PLB mRNA，并使β1-ARmRNA不稳定。HuR-PLB和HuR-β1-AR调节过程对ISO诱导的心脏重塑有影响。跨界性PLB是SERCA2A的可逆抑制剂，对于SR Ca2 +隔离，从而使心肌细胞的兴奋-收缩偶联和心肌重塑至关重要。β1-AR-cAMP-PKA途径可通过PKA介导的蛋白磷酸化抑制PLB的活性。本研究表明HuR能够通过调节PLB和β1-AR的表达来调节心脏重塑。这些发现揭示了控制心肌重塑的新颖机制，并可能为干预人类心脏重塑相关心脏疾病的策略提供新线索。