Ren Changzhen, Sun Kaiqiang, Zhang Yanda, Hu Yangxi, Hu Bowen, Zhao Jian, He Zhiqing, Ding Ru, Wang Weizhong, Liang Chun
Department of Cardiology, Changzheng Hospital, Naval Medical University, Shanghai, China.
Department of General Practice, 960th Hospital of PLA, Jinan, China.
Front Pharmacol. 2021 Apr 29;12:664181. doi: 10.3389/fphar.2021.664181. eCollection 2021.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to decrease the adverse cardiac events and risks of cardiovascular mortality among patients with or without diabetes, which has made these drugs promising treatment options for patients with chronic heart failure. Cardiac dysfunction is a common and severe side effect induced by cancer chemotherapies, which seriously affects the prognosis and life quality of tumor patients. However, it is not clear whether SGLT2 inhibitors have cardiovascular benefits in patients with cancer chemotherapy-related cardiac dysfunction. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role against sunitinib (SNT)-induced cardiac dysfunction in a mouse model. Male C57BL/6J mice were randomized into control (control, = 8), empagliflozin (EMPA, = 8), sunitinib (SNT, = 12), or sunitinib and empagliflozin coadministration (SNT + EMPA, = 12) groups. EMPA, SNT, or SNT-combined EMPA was given oral gavage for consecutive 28 days. Cardiovascular functions and pathological changes were examined, and the underlying mechanisms of EMPA's effects were investigated in H9c2 cardiomyocytes. Mice in the SNT group exhibited dramatically elevated blood pressure (systolic blood pressure [SBP] 134.30 ± 6.455 mmHg vs. 114.85 ± 6.30 mmHg) and impaired left ventricular function (left ventricular ejection fraction [LVEF] 50.24 ± 3.06% vs. 84.92 ± 2.02%), as compared with those of the control group. However, EMPA could ameliorate SNT-induced cardiotoxicity, both in terms of SBP (117.51 ± 5.28 mmHg vs. 134.30 ± 6.455 mmHg) and LVEF (76.18 ± 5.16% vs. 50.24 ± 3.06 %). In H9c2 cardiomyocytes, SNT-induced cardiomyocyte death and cell viability loss as well as dysfunction of adenosine 5'-monophosphate-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling-mediated autophagy were restored by EMPA. However, these favorable effects mediated by EMPA were blocked by the inhibition of AMPK or autophagy. EMPA could ameliorate SNT-induced cardiac dysfunction regulating cardiomyocyte autophagy, which was mediated by the AMPK-mTOR signaling pathway. These findings supported that SGLT2 inhibitor therapy could be a potential cardioprotective approach for cardiovascular complications among patients receiving SNT. However, these favorable effects still need to be validated in clinical trials.
钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂已被证明可降低糖尿病患者或非糖尿病患者的不良心脏事件及心血管死亡风险，这使得这些药物成为慢性心力衰竭患者有前景的治疗选择。心脏功能障碍是癌症化疗引起的常见且严重的副作用，严重影响肿瘤患者的预后和生活质量。然而，尚不清楚SGLT2抑制剂对癌症化疗相关心脏功能障碍患者是否具有心血管益处。我们旨在确定SGLT2抑制剂恩格列净（EMPA）在小鼠模型中对舒尼替尼（SNT）诱导的心脏功能障碍是否具有保护作用。将雄性C57BL/6J小鼠随机分为对照组（对照，n = 8）、恩格列净组（EMPA，n = 8）、舒尼替尼组（SNT，n = 12）或舒尼替尼与恩格列净联合给药组（SNT + EMPA，n = 12）。连续28天经口灌胃给予EMPA、SNT或SNT联合EMPA。检测心血管功能和病理变化，并在H9c2心肌细胞中研究EMPA作用的潜在机制。与对照组相比，SNT组小鼠的血压显著升高（收缩压[SBP] 134.30±6.455 mmHg对114.85±6.30 mmHg），左心室功能受损（左心室射血分数[LVEF] 50.24±3.06%对84.92±2.02%）。然而，EMPA可改善SNT诱导的心脏毒性，无论是SBP（117.51±5.28 mmHg对134.30±6.455 mmHg）还是LVEF（76.18±5.16%对50.24±3.06%）。在H9c2心肌细胞中，EMPA可恢复SNT诱导的心肌细胞死亡、细胞活力丧失以及5'-单磷酸腺苷激活蛋白激酶-雷帕霉素哺乳动物靶标（AMPK-mTOR）信号介导的自噬功能障碍。然而，EMPA介导的这些有益作用被AMPK抑制或自噬抑制所阻断。EMPA可通过调节心肌细胞自噬来改善SNT诱导的心脏功能障碍，这是由AMPK-mTOR信号通路介导的。这些发现支持SGLT2抑制剂治疗可能是接受SNT治疗的患者心血管并发症的一种潜在心脏保护方法。然而，这些有益作用仍需在临床试验中得到验证。
