Institute of Toxicology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Division of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Biochem Pharmacol. 2019 Jun;164:82-93. doi: 10.1016/j.bcp.2019.03.038. Epub 2019 Mar 29.
Cardiotoxicity is the dose limiting adverse effect of anthracycline-based anticancer therapy. Inhibitor studies point to Rac1 as therapeutic target to prevent anthracycline-induced cardiotoxicity. Yet, supporting genetic evidence is still missing and the pathophysiological relevance of different cardiac cell types is unclear. Here, we employed a tamoxifen-inducible cardiomyocyte-specific rac1 knock-out mouse model (Rac1) to investigate the impact of Rac1 expression in cardiomyocytes on cardiac injury following doxorubicin treatment. Distinctive stress responses resulting from doxorubicin treatment were observed, including upregulation of systemic markers of inflammation (IL-6, IL-1α, MCP-1), cardiac damage (ANP, BNP), DNA damage (i.e. DNA double-strand breaks (DSB)), DNA damage response (DDR) and cell death. Measuring the acute doxorubicin response, the serum level of MCP-1 was elevated, cardiac mRNA expression of Hsp70 was reduced and cardiac DDR was specifically enhanced in Rac1 deficient mice. The frequency of apoptotic heart cells remained unaffected by Rac1. Employing a subactue model, the number of doxorubicin-induced DSB was significantly reduced if Rac1 is absent. Yet, the doxorubicin-triggered increase in serum ANP and BNP levels remained unaffected by Rac1. Overall, knock-out of rac1 in cardiomyocytes confers partial protection against doxorubicin-induced cardiac injury. Hence, the data provide first genetic evidence supporting the view that pharmacological targeting of Rac1 is useful to widen the therapeutic window of anthracycline-based anticancer therapy by alleviating acute/subacute cardiomyocyte damage. Furthermore, considering published data obtained from the use of pharmacological Rac1 inhibitors, the results of our study indicate that Rac1-regulated functions of cardiac cell types others than cardiomyocytes additionally influence the adverse outcomes of anthracycline treatment on the heart.
心脏毒性是基于蒽环类抗癌药物治疗的剂量限制不良效应。抑制剂研究表明 Rac1 是预防蒽环类药物诱导的心脏毒性的治疗靶点。然而，目前仍缺乏支持的遗传证据，并且不同心脏细胞类型的病理生理相关性尚不清楚。在这里，我们使用了一种他莫昔芬诱导的心肌细胞特异性 rac1 敲除小鼠模型（Rac1）来研究心肌细胞中 Rac1 表达对阿霉素治疗后心脏损伤的影响。观察到阿霉素处理后出现了明显的应激反应，包括全身炎症标志物（IL-6、IL-1α、MCP-1）、心脏损伤（ANP、BNP）、DNA 损伤（即 DNA 双链断裂（DSB））、DNA 损伤反应（DDR）和细胞死亡的上调。在测量急性阿霉素反应时，MCP-1 的血清水平升高，Hsp70 的心脏 mRNA 表达降低，并且 Rac1 缺陷小鼠的心脏 DDR 特异性增强。Rac1 缺失对心脏细胞凋亡的频率没有影响。在亚急性模型中，如果 Rac1 不存在，则阿霉素诱导的 DSB 数量显著减少。然而，Rac1 对阿霉素引发的血清 ANP 和 BNP 水平升高没有影响。总的来说，心肌细胞中 rac1 的敲除赋予了对阿霉素诱导的心脏损伤的部分保护。因此，该数据提供了第一个遗传证据，支持通过减轻急性/亚急性心肌细胞损伤来靶向 Rac1 的药理学方法拓宽基于蒽环类的抗癌治疗的治疗窗口的观点。此外，考虑到使用药理学 Rac1 抑制剂获得的已发表数据，我们的研究结果表明，除了心肌细胞以外的心脏细胞类型的 Rac1 调节功能还会影响蒽环类药物治疗对心脏的不良后果。
