Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
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<b>Context:</b> Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its potential effects in SU-induced cardiotoxicity have not been investigated. <b>Objective:</b> This study investigates the effect of TMZ in sunitinib-induced cardiotoxicity <i>in vivo</i> and <i>in vitro</i> and molecular mechanisms. <b>Materials and methods:</b> Male 129S1/SvImJ mice were treated with vehicle, SU (40 mg/kg/d) or SU and TMZ (20 mg/kg/d) via oral gavage for 28 days, and cardiovascular functions and cardiac protein expressions were examined. H9c2 cardiomyocytes were treated with vehicle, SU (2–10 μM) or SU and TMZ (40–120 μM) for 48 h, and cell viability, apoptosis, autophagy, and protein expression was tested. <b>Results:</b> SU induces hypertension (systolic blood pressure [SBP] + 28.33 ± 5.00 mmHg) and left ventricular dysfunction (left ventricular ejection fraction [LVEF] − 11.16 ± 2.53%) in mice. In H9c2 cardiomyocytes, SU reduces cell viability (IC<sub>50</sub> 4.07 μM) and inhibits the AMPK/mTOR/autophagy pathway (<i>p</i> < 0.05). TMZ co-administration with SU reverses SU-induced cardiotoxicity in mice (SBP − 23.75 ± 4.69 mmHg, LVEF + 10.95 ± 3.317%), alleviates cell viability loss in H9c2 cardiomyocytes (<i>p</i> < 0.01) and activates the AMPK/mTOR/autophagy pathway <i>in vivo</i> (<i>p</i> < 0.001) and <i>in vitro</i> (<i>p</i> < 0.05). <b>Discussion and conclusions:</b> Our results suggest TMZ as a potential cardioprotective approach for cardiovascular complications during SU regimen, and potentially for cardiotoxicity of other anticancer chemotherapies associated with cardiomyocyte autophagic pathways.
<b>背景：</b> 舒尼替尼（Sunitinib，SU）是一种多靶点酪氨酸激酶抑制剂类抗肿瘤药物，其临床应用常因心血管并发症而受限。曲美他嗪（Trimetazidine，TMZ）作为抗心绞痛药物，已被证实可在多种心血管疾病中发挥心脏保护作用，但目前尚未有研究探索其对舒尼替尼诱导的心肌毒性的潜在干预效果。<b>研究目的：</b> 本研究旨在探讨曲美他嗪对舒尼替尼诱导的心肌毒性的体内（in vivo）与体外（in vitro）干预效应及其分子机制。<b>材料与方法：</b> 选取雄性129S1/SvImJ小鼠，通过灌胃给药分别给予溶剂对照、舒尼替尼（40mg/kg/d）或舒尼替尼联合曲美他嗪（20mg/kg/d），连续干预28天，随后检测小鼠心血管功能及心脏蛋白质表达水平。采用H9c2心肌细胞，分别给予溶剂对照、舒尼替尼（2~10μM）或舒尼替尼联合曲美他嗪（40~120μM）处理48小时，检测细胞活力、凋亡、自噬及蛋白质表达情况。<b>研究结果：</b> 舒尼替尼可诱导小鼠出现高血压，其收缩压（systolic blood pressure, SBP）升高28.33±5.00mmHg，同时引发左心室功能障碍，左心室射血分数（left ventricular ejection fraction, LVEF）降低11.16±2.53%。在H9c2心肌细胞中，舒尼替尼可降低细胞活力，半数抑制浓度（half maximal inhibitory concentration, IC₅₀）为4.07μM，同时抑制AMPK/mTOR/自噬通路（p<0.05）。联合给予曲美他嗪可逆转小鼠体内舒尼替尼诱导的心肌毒性：SBP降低23.75±4.69mmHg，LVEF升高10.95±3.317%；同时可缓解H9c2心肌细胞的活力损失（p<0.01），并在体内（p<0.001）与体外（p<0.05）均激活AMPK/mTOR/自噬通路。<b>讨论与结论：</b> 本研究结果显示，曲美他嗪有望成为舒尼替尼治疗期间心血管并发症的潜在心脏保护策略，同时也可能对其他与心肌细胞自噬通路相关的抗肿瘤化疗药物诱导的心肌毒性具有干预价值。
