卡非佐米是一种不可逆的蛋白酶体抑制剂,用于多发性骨髓瘤患者。然而,卡非佐米治疗与心血管并发症有关。Empagliflozin,钠葡萄糖协同转运蛋白2抑制剂(SGLT-2)抑制剂,是一种口服抗糖尿病药物,具有抗氧化和抗炎特性。本研究的目的是确定依帕格列净对卡非佐米诱导的心脏毒性的心脏保护作用。C57BL/6小鼠随机分为四组:对照组,empagliflozin,Carfilzomib,和carfilzomib+empagliflozin。Empagliflozin通过改善组织学改变来预防卡非佐米诱导的心脏毒性,CK-MB,和肌钙蛋白-I此外,它通过对过氧化氢酶活性的作用抑制卡非佐米诱导的氧化损伤和炎症,降低谷胱甘肽水平和超氧化物歧化酶活性,和降低核因子-κB(p65)和细胞因子水平。机械上,empagliflozin消除了卡非佐米诱导的内质网应激,如通过对葡萄糖调节蛋白-78(GRP-78)/活化转录因子6(ATF6)/C/EBP同源蛋白(CHOP)轴的作用所证明的。有趣的是,卡非佐米显著诱导自噬,empagliflozin进一步增强了这种效果,LC3B和beclin-1mRNA表达增加,p62表达减少。通过降低活性caspase-3的表达证实了依帕格列净对细胞凋亡的影响。重要的是,依帕列净未改变卡非佐米对人U266B1多发性骨髓瘤细胞的细胞毒作用.我们的研究结果表明,empagliflozin可能为减轻多发性骨髓瘤患者卡非佐米引起的心脏毒性提供一种新的治疗策略.
Carfilzomib is an irreversible proteasome inhibitor used for multiple myeloma patients. However,
carfilzomib treatment is associated with cardiovascular complications. Empagliflozin, an Sodium Glucose Co-transporter 2 inhibitor (SGLT-2) inhibitor, is an oral antidiabetic drug with proven antioxidant and anti-inflammatory properties. The aim of the present study was to determine the cardioprotective effects of empagliflozin against carfilzomib-induced cardiotoxicity. C57BL/6 mice were randomly divided into four groups: control, empagliflozin,
carfilzomib, and
carfilzomib + empagliflozin. Empagliflozin prevented
carfilzomib-induced cardiotoxicity by ameliorating histological alterations, CK-MB, and troponin-I. Moreover, it inhibited
carfilzomib-induced oxidative damage and inflammation via its action on catalase activity, reduced glutathione levels and superoxide dismutase activity, and reduced nuclear factor-κB (p65) and cytokine levels. Mechanistically, empagliflozin abrogated endoplasmic reticulum stress induced by carfilzomib, as evidenced by the effect on the Glucose Regulated Protein-78 (GRP-78)/Activating Transcription Factor 6 (ATF6)/C/EBP homologous protein (CHOP) axis. Intriguingly, carfilzomib significantly induced autophagy, an effect that was further enhanced by empagliflozin, evidenced by increased LC3B and beclin-1 mRNA expression and reduced p62 expression. The effect of empagliflozin on apoptosis was confirmed by reduced expression of active caspase-3. Importantly, empagliflozin did not alter the cytotoxic effect of carfilzomib on human U266B1 multiple myeloma cells. our findings suggest that empagliflozin may provide a new therapeutic strategy to mitigate carfilzomib-induced cardiotoxicity in multiple myeloma patients.