Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN 55455, USA; Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Egypt.
Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN 55455, USA.
Biomed Pharmacother. 2024 Oct;179:117288. doi: 10.1016/j.biopha.2024.117288. Epub 2024 Aug 14.
Irreversible cardiotoxicity limits the clinical application of doxorubicin (DOX). DOX-induced cardiotoxicity has been associated with induction of senescence and activation of the p38 MAPK pathway. Losmapimod (LOSM), an orally active p38 MAPK inhibitor, is an anti-inflammatory agent with cardioprotective effects. Nevertheless, the effect of LOSM against DOX-induced cardiotoxicity has not been reported. In this study, we determined the effects of LOSM on DOX-induced chronic cardiotoxicity in C57BL/6 N mice. Five-week-old C57BL/6 N mice were fed diet containing LOSM (estimated daily intake 12 mg/kg/day) or a control diet for four days. Thereafter, mice were randomized to receive six weekly intraperitoneal injections of either DOX (4 mg/kg) or saline. Three days after the last injection, cardiac function was assessed by trans-thoracic echocardiography. Activation of p38, JNK, and ERK1/2 MAPKs were assessed by immunoblotting in the heart and liver. Gene expressions of senescence, inflammatory, oxidative stress, and mitochondrial function markers were quantified using real-time PCR and serum inflammatory markers were assessed by Luminex. Our results demonstrated that LOSM attenuated p38 MAPK activation, ameliorated DOX-induced cardiac dysfunction, and abrogated DOX-induced expression of the senescence marker p21. Additionally, LOSM demonstrated anti-inflammatory effects, with reduced cardiac Il-1α and Il-6 gene expression in DOX-treated mice. Systemic inflammation, assessed by serum cytokine levels, showed decreased IL-6 and CXCL1 in both DOX-treated mice and mice on LOSM diet. LOSM significantly increased mitofusin2 gene expression, which may enhance mitochondrial fusion. These findings underscore the potential therapeutic efficacy of p38 MAPK inhibition, exemplified by LOSM, in ameliorating DOX-induced cardiotoxicity, senescence, and inflammation.
阿霉素（DOX）的不可逆性心脏毒性限制了其临床应用。DOX 诱导的心脏毒性与衰老的诱导和 p38 MAPK 通路的激活有关。Losmapimod（LOSM）是一种具有抗炎作用的口服 p38 MAPK 抑制剂，具有心脏保护作用。然而，LOSM 对 DOX 诱导的心脏毒性的作用尚未见报道。在本研究中，我们确定了 LOSM 对 C57BL/6N 小鼠 DOX 诱导的慢性心脏毒性的影响。将 5 周龄的 C57BL/6N 小鼠用含 LOSM（估计每日摄入量 12mg/kg/天）的饮食或对照饮食喂养 4 天。此后，将小鼠随机分为接受六次每周一次的 DOX（4mg/kg）或生理盐水腹腔注射。最后一次注射后 3 天，通过经胸超声心动图评估心脏功能。通过免疫印迹法在心脏和肝脏中评估 p38、JNK 和 ERK1/2 MAPK 的激活。使用实时 PCR 定量测定衰老、炎症、氧化应激和线粒体功能标志物的基因表达，并通过 Luminex 评估血清炎症标志物。我们的结果表明，LOSM 可减轻 p38 MAPK 的激活，改善 DOX 诱导的心脏功能障碍，并阻断 DOX 诱导的衰老标志物 p21 的表达。此外，LOSM 具有抗炎作用，可降低 DOX 处理小鼠心脏中 Il-1α 和 Il-6 基因的表达。通过血清细胞因子水平评估的全身炎症显示，DOX 处理的小鼠和 LOSM 饮食的小鼠的 IL-6 和 CXCL1 均减少。LOSM 显著增加了线粒体融合蛋白 2 基因的表达，这可能增强了线粒体融合。这些发现强调了 p38 MAPK 抑制的潜在治疗效果，以 LOSM 为例，可改善 DOX 诱导的心脏毒性、衰老和炎症。
