Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
J Mol Cell Cardiol. 2011 Sep;51(3):318-28. doi: 10.1016/j.yjmcc.2011.05.010. Epub 2011 May 23.
Clinical use of the antineoplastic agent doxorubicin (DOX) is limited by its cardiomyocyte toxicity. Attempts to decrease cardiomyocyte injury showed promising results in vitro, but failed to reduce the adverse effects of DOX in vivo, suggesting that other mechanisms contribute to its cardiotoxicity as well. Evidence that DOX also induces cardiac injury by compromising extracellular matrix integrity is lacking. The matricellular protein thrombospondin-2 (TSP-2) is known for its matrix-preserving function, and for modulating cellular function. Here, we investigated whether TSP-2 modulates the process of doxorubicin-induced cardiomyopathy (DOX-CMP). TSP-2-knockout (TSP-2-KO) and wild-type (WT) mice were treated with DOX (2 mg/kg/week) for 12 weeks to induce DOX-CMP. Mortality was significantly increased in TSP-2-KO compared to WT mice. Surviving DOX-treated TSP-2-KO mice had depressed cardiac function compared to WT animals, accompanied by increased cardiomyocyte apoptosis and matrix damage. Enhanced myocyte damage in the absence of TSP-2 was associated with impaired activation of the Akt signaling pathway in TSP-2-KO compared to WT. The absence of TSP-2, in vivo and in vitro, reduced Akt activation both under non-treated conditions and after DOX. Importantly, inhibition of Akt phosphorylation in cardiomyocytes significantly reduced TSP-2 expression, unveiling a unique feedback loop between Akt and TSP-2. Finally, enhanced matrix disruption in DOX-treated TSP-2-KO hearts went along with increased matrix metalloproteinase-2 levels. Taken together, this study is the first to provide evidence for the implication of the matrix element TSP-2 in protecting against DOX-induced cardiac injury and dysfunction.
抗肿瘤药物阿霉素（DOX）的临床应用受到其心肌细胞毒性的限制。减少心肌细胞损伤的尝试在体外显示出有希望的结果，但未能降低 DOX 在体内的不良反应，这表明其他机制也导致了其心脏毒性。缺乏 DOX 也通过损害细胞外基质完整性来诱导心脏损伤的证据。细胞外基质蛋白血小板反应蛋白-2（TSP-2）以其维持基质的功能和调节细胞功能而闻名。在这里，我们研究了 TSP-2 是否调节阿霉素诱导的心肌病（DOX-CMP）的过程。TSP-2 敲除（TSP-2-KO）和野生型（WT）小鼠用 DOX（2mg/kg/周）处理 12 周以诱导 DOX-CMP。与 WT 小鼠相比，TSP-2-KO 小鼠的死亡率显著增加。与 WT 动物相比，存活的 DOX 处理的 TSP-2-KO 小鼠的心脏功能下降，伴有心肌细胞凋亡和基质损伤增加。在缺乏 TSP-2 的情况下，肌细胞损伤增强与 WT 相比，TSP-2-KO 中 Akt 信号通路的激活受损有关。在体内和体外，缺乏 TSP-2 均可降低 Akt 的激活，无论是在未处理条件下还是在 DOX 处理后。重要的是，心肌细胞中 Akt 磷酸化的抑制显著降低了 TSP-2 的表达，揭示了 Akt 和 TSP-2 之间的独特反馈环。最后，在 DOX 处理的 TSP-2-KO 心脏中，基质破坏的增强伴随着基质金属蛋白酶-2 水平的增加。总之，这项研究首次提供了证据，证明细胞外基质元件 TSP-2 在保护 DOX 诱导的心脏损伤和功能障碍方面具有重要作用。
