Heat shock protein 20 interacting with phosphorylated Akt reduces doxorubicin-triggered oxidative stress and cardiotoxicity.
Heat shock protein 20 interacting with phosphorylated Akt reduces doxorubicin-triggered oxidative stress and cardiotoxicity.
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DOI：
10.1161/circresaha.108.182832
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发表时间：
2008-11-21
影响因子：
20.1
通讯作者：
Kranias EG
中科院分区：
文献类型：
--
作者：
Fan GC;Zhou X;Wang X;Song G;Qian J;Nicolaou P;Chen G;Ren X;Kranias EG
阿霉素（DOX）是一种广泛应用的抗肿瘤药物，但其应用因心脏毒性副作用而受限。近期研究表明，热休克蛋白20（Hsp20）可保护心肌细胞免受由缺血/再灌注损伤或长时间β - 肾上腺素能受体激动剂刺激所诱导的凋亡。然而，Hsp20是否会对阿霉素诱导的心脏损伤发挥类似的保护作用尚不清楚。实际上，阿霉素治疗与心脏中Hsp20的下调有关。为阐明Hsp20在阿霉素引发的心脏毒性中的作用，首先通过腺病毒介导的基因传递在体外过表达Hsp20。与绿色荧光蛋白（GFP）对照组相比，Hsp20水平升高使细胞对阿霉素诱导的死亡具有更高的抵抗力。此外，体内心脏特异性过表达Hsp20显著改善了阿霉素引发的急性心肌细胞凋亡和动物死亡率。Hsp20转基因小鼠在长期给予阿霉素后也表现出心脏功能改善和生存期延长。这些有益作用的潜在机制与Akt磷酸化/活性的维持以及阿霉素诱导的氧化应激的减轻有关。免疫共沉淀研究揭示了Hsp20和磷酸化Akt之间的相互作用。相应地，在阿霉素处理的Hsp20转基因小鼠心脏中，BAD磷酸化得以维持，裂解的半胱天冬酶 - 3减少，这与Hsp20的抗凋亡作用一致。平行的体外实验表明，用显性负性Akt腺病毒感染心肌细胞或用PI3 - 激酶抑制剂预孵育心肌细胞，都会显著减弱Hsp20的保护作用。综上所述，我们的研究结果表明，Hsp20的过表达抑制阿霉素引发的心脏损伤，并且这些有益作用似乎依赖于Akt的激活。因此，Hsp20可能成为减轻癌症患者阿霉素治疗心脏毒性作用的一个新的治疗靶点。
Doxorubicin (DOX) is a widely used antitumor drug, but its application is limited due to its cardiotoxic side effects. Hsp20 has been recently shown to protect cardiomyocytes against apoptosis, induced by ischemia/reperfusion injury or by prolonged β-agonist stimulation. However, it is not clear whether Hsp20 would exert similar protective effects against DOX-induced cardiac injury. Actually, DOX-treatment was associated with down-regulation of Hsp20 in the heart. To elucidate the role of Hsp20 in DOX-triggered cardiac toxicity, Hsp20 was first overexpressed ex vivo by adenovirus-mediated gene delivery. Increased Hsp20 levels conferred higher resistance to DOX-induced cell death, compared to GFP-control. Furthermore, cardiac-specific overexpression of Hsp20 in vivo significantly ameliorated acute DOX-triggered cardiomyocyte apoptosis and animal mortality. Hsp20-transgenic mice also showed improved cardiac function and prolonged survival after chronic administration of DOX. The mechanisms underlying these beneficial effects were associated with preserved Akt phosphorylation/activity and attenuation of DOX-induced oxidative stress. Co-immunoprecipitation studies revealed an interaction between Hsp20 and phosphorylated Akt. Accordingly, BAD phosphorylation was preserved and cleaved caspase-3 was decreased in DOX-treated Hsp20-TG hearts, consistent with the Hsp20's anti-apoptotic effects. Parallel ex vivo experiments showed that either infection with a dominant-negative Akt adenovirus or pre-incubation of cardiomyocytes with the PI3-kinase inhibitors significantly attenuated the protective effects of Hsp20. Taken together, our findings indicate that overexpression of Hsp20 inhibits DOX-triggered cardiac injury, and these beneficial effects appear to be dependent on Akt activation. Thus, Hsp20 may constitute a new therapeutic target in ameliorating the cardiotoxic effects of DOX-treatment in cancer patients.