Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress.
Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress.
复制标题
Dapagliflozin 通过激活 SIRT1 和抑制内质网应激来减轻压力超负荷诱导的小鼠心肌重塑。
DOI：
10.1038/s41401-021-00805-2
复制
发表时间：
2021
影响因子：
8.2
通讯作者：
Li Lei
中科院分区：
文献类型：
--
作者：
Ren Fang-Fang;Xie Zuo-Yi;Jiang Yi-Na;Guan Xuan;Chen Qiao-Ying;Lai Teng-Fang;Li Lei
内质网应激介导的细胞凋亡在心力衰竭的发生、发展中起着至关重要的作用。达格列净（DAPA）是一种新型钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂，是一种口服降糖药，可减少肾脏对葡萄糖的重吸收，增加尿液中葡萄糖的排泄。研究表明，DAPA 除了控制血糖外，还可能具有治疗心力衰竭的潜力。本研究探讨DAPA对心力衰竭引起的内质网应激相关细胞凋亡的影响。在体外，我们发现 DAPA 抑制血管紧张素 II (Ang II) 处理的心肌细胞中裂解的 caspase 3、Bax、C/EBP 同源蛋白 (CHOP) 和葡萄糖调节蛋白 78 (GRP78) 的表达，并上调心肌保护蛋白 Bcl-2。此外，DAPA 还能促进沉默信息调节因子 2 相关酶 1 (SIRT1) 的表达，并抑制激活转录因子 4 (ATF4) 的表达以及 p-PERK/PERK 和 p-eIF2α/eIF2α 的比率。值得注意的是，DAPA 的治疗效果因 SIRT1 抑制剂 EX527 (10μM) 预处理而减弱。同时给予DAPA可抑制Ang II诱导的成纤维细胞向肌成纤维细胞的转化，并抑制成纤维细胞的迁移。总之，我们目前的研究结果首先表明，DAPA 可以通过激活 Ang II 处理的心肌细胞中的 SIRT1 来抑制 ER 应激反应的 PERK-eIF2α-CHOP 轴，并改善体内心力衰竭的发展。
Endoplasmic reticulum stress-mediated apoptosis plays a vital role in the occurrence and development of heart failure. Dapagliflozin (DAPA), a new type of sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an oral hypoglycemic drug that reduces glucose reabsorption by the kidneys and increases glucose excretion in the urine. Studies have shown that DAPA may have the potential to treat heart failure in addition to controlling blood sugar. This study explored the effect of DAPA on endoplasmic reticulum stress-related apoptosis caused by heart failure. In vitro, we found that DAPA inhibited the expression of cleaved caspase 3, Bax, C/EBP homologous protein (CHOP), and glucose-regulated protein78 (GRP78) and upregulated the cardiomyoprotective protein Bcl-2 in angiotensin II (Ang II)-treated cardiomyocytes. In addition, DAPA promoted the expression of silent information regulator factor 2-related enzyme 1 (SIRT1) and suppressed the expression of activating transcription factor 4 (ATF4) and the ratios p-PERK/PERK and p-eIF2α/eIF2α. Notably, the therapeutic effect of DAPA was weakened by pretreatment with the SIRT1 inhibitor EX527 (10 μM). Simultaneous administration of DAPA inhibited the Ang II-induced transformation of fibroblasts into myofibroblasts and inhibited fibroblast migration. In summary, our present findings first indicate that DAPA could inhibit the PERK-eIF2α-CHOP axis of the ER stress response through the activation of SIRT1 in Ang II-treated cardiomyocytes and ameliorate heart failure development in vivo.