Department of Cardiology, Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
Department of Cardiology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, China.
Acta Pharmacol Sin. 2022 Jul;43(7):1721-1732. doi: 10.1038/s41401-021-00805-2. Epub 2021 Dec 1.
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.
内质网应激介导的细胞凋亡在心力衰竭的发生和发展中起着至关重要的作用。达格列净（DAPA）是一种新型的钠-葡萄糖共转运蛋白 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，增加尿液中的葡萄糖排泄。研究表明，除了控制血糖外，DAPA 可能还有治疗心力衰竭的潜力。本研究探讨了 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 抑制了血管紧张素 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，并上调了心肌保护蛋白 Bcl-2。此外，DAPA 促进了沉默信息调节因子 2 相关酶 1（SIRT1）的表达，并抑制了激活转录因子 4（ATF4）和 p-PERK/PERK 和 p-eIF2α/eIF2α 的比值的表达。值得注意的是，用 SIRT1 抑制剂 EX527（10 μM）预处理会削弱 DAPA 的治疗效果。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，并抑制成纤维细胞迁移。总之，我们的研究结果首次表明，DAPA 可通过激活 SIRT1 抑制 Ang II 处理的心肌细胞内质网应激反应中的 PERK-eIF2α-CHOP 轴，并改善体内心力衰竭的发展。
