Possible involvement of downregulation of the apelin-APJ system in doxorubicin-induced cardiotoxicity
Possible involvement of downregulation of the apelin-APJ system in doxorubicin-induced cardiotoxicity
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DOI：
10.1152/ajpheart.00703.2013
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发表时间：
2015-04-15
影响因子：
4.8
通讯作者：
Fukamizu, Akiyoshi
中科院分区：
文献类型：
--
作者：
Hamada, Juri;Baasanjav, Altansarnai;Fukamizu, Akiyoshi
Apelin多肽是APJ的内源性配体，APJ是一种与血管紧张素II 1型受体相关的受体蛋白，APJ是G蛋白偶联受体超家族的成员，具有7个跨膜区。最近的研究结果表明，apelin-APJ系统在心脏收缩和心脏保护中发挥着潜在的作用。在本研究中，我们发现在阿霉素(Dox)诱导的心脏毒性中，apelin-APJ系统被破坏。在给药后第1天和第5天(20 mg/kg ip)，我们发现C57BL/6J小鼠心脏apelin和APJ基因表达下调。注射Dox后第5天，血浆apelin水平和心脏APJ蛋白表达均显著下降。心脏apelin含量在注射Dox后第1天下降，第5天回升至基础水平。我们还研究了APJ基因缺失对Dox诱导的心脏毒性的影响。与野生型小鼠相比，APJ基因敲除小鼠在Dox(15 mg/kg ip)治疗后第5天表现出明显的心肌收缩能力抑制，随后14天存活率下降。此外，在APJ基因敲除小鼠中，Dox诱导的心肌损伤、心肌蛋白羰化和自噬功能障碍加速。大鼠心肌H9c2细胞表现出Dox诱导的存活率下降，APJ过表达及与apelin联合治疗可阻止这种下降。这些结果提示，Dox对APJ表达的抑制可能加剧了Dox的心脏毒性，这可能是内源性APJ系统保护功能下降的原因之一。APELIN-APJ系统的调节有望用于治疗Dox所致的心脏毒性。
Apelin peptide is an endogenous ligand of APJ (a putative receptor protein related to the angiotensin II type 1 receptor), which is a member of a G protein-coupled receptor superfamily with seven transmembrane domains. Recent findings have suggested that the apelin-APJ system plays a potential role in cardiac contraction and cardioprotection. In the present study, we show that the apelin-APJ system is disrupted in doxorubicin (Dox)-induced cardiotoxicity. We found downregulation of apelin and APJ mRNA expression in C57Bl/6J mouse hearts on days 1 and 5 after Dox administration (20 mg/kg ip). Plasma apelin levels and cardiac APJ protein expression were significantly decreased on day 5 after Dox injection. Cardiac apelin contents were reduced on day 1 but increased to basal levels on day 5 after Dox injection. We also examined the effects of APJ gene deletion on Dox-induced cardiotoxicity. Compared with wild-type mice, APJ knockout mice showed a significant depression in cardiac contractility on day 5 after Dox (15 mg/kg ip) treatment followed by a decrease in 14-day survival rates. Moreover, Dox-induced myocardial damage, cardiac protein carbonylation, and autophagic dysfunction were accelerated in APJ knockout mice. Rat cardiac H9c2 cells showed Dox-induced decreases in viability, which were prevented by APJ overexpression and the combination with apelin treatment. These results suggest that the suppression of APJ expression after Dox administration can exacerbate Dox-induced cardiotoxicity, which may be responsible for depressed protective function of the endogenous apelin-APJ system. Modulation of the apelin-APJ system may hold promise for the treatment of Dox-induced cardiotoxicity.