Lin Ke, Yang Na, Luo Wu, Qian Jin-Fu, Zhu Wei-Wei, Ye Shi-Ju, Yuan Chen-Xin, Xu Di-Yun, Liang Guang, Huang Wei-Jian, Shan Pei-Ren
Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
Acta Pharmacol Sin. 2022 Oct;43(10):2624-2635. doi: 10.1038/s41401-022-00885-8. Epub 2022 Feb 25.
Obesity is an important independent risk factor for cardiovascular diseases, remaining an important health concern worldwide. Evidence shows that saturated fatty acid-induced inflammation in cardiomyocytes contributes to obesity-related cardiomyopathy. Dapagliflozin (Dapa), a selective SGLT2 inhibitor, exerts a favorable preventive activity in heart failure. In this study, we investigated the protective effect of Dapa against cardiomyopathy caused by high fat diet-induced obesity in vitro and in vivo. Cultured rat cardiomyocyte H9c2 cells were pretreated with Dapa (1, 2.5 μM) for 1.5 h, followed by treatment with palmitic acid (PA, 200 μM) for 24 h. We showed that Dapa pretreatment concentration-dependently attenuated PA-induced cell hypertrophy, fibrosis and apoptosis. Transcriptome analysis revealed that inhibition of PA-activated MAPK/AP-1 pathway contributed to the protective effect of Dapa in H9c2 cells, and this was confirmed by anti-p-cJUN fluorescence staining assay. Using surface plasmon resonance analysis we found the direct binding of Dapa with NHE1. Gain and loss of function experiments further demonstrated the role of NHE1 in the protection of Dapa. In vivo experiments were conducted in mice fed a high fat diet for 5 months. The mice were administered Dapa (1 mg·kg·d, i.g.) in the last 2 months. Dapa administration significantly reduced the body weight and improved the serum lipid profiles. Dapa administration also alleviated HFD-induced cardiac dysfunction and cardiac aberrant remodeling via inhibiting MAPK/AP-1 pathway and ameliorating cardiac inflammation. In conclusion, Dapa exerts a direct protective effect against saturated fatty acid-induced cardiomyocyte injury in addition to the lowering effect on serum lipids. The protective effect results from negative regulating MAPK/AP-1 pathway in a NHE1-dependent way. The current study highlights the potential of clinical use of Dapa in the prevention of obesity-related cardiac dysfunction.
肥胖是心血管疾病的一个重要独立危险因素，在全球范围内仍是一个重要的健康问题。有证据表明，饱和脂肪酸诱导的心肌细胞炎症会导致肥胖相关性心肌病。达格列净（Dapa）是一种选择性钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂，在心力衰竭中具有良好的预防作用。在本研究中，我们在体外和体内研究了Dapa对高脂饮食诱导的肥胖所致心肌病的保护作用。将培养的大鼠心肌细胞H9c2细胞用Dapa（1、2.5 μM）预处理1.5小时，然后用棕榈酸（PA，200 μM）处理24小时。我们发现Dapa预处理呈浓度依赖性地减轻了PA诱导的细胞肥大、纤维化和凋亡。转录组分析显示，抑制PA激活的丝裂原活化蛋白激酶/激活蛋白-1（MAPK/AP-1）途径有助于Dapa对H9c2细胞的保护作用，抗磷酸化c-JUN荧光染色试验证实了这一点。通过表面等离子体共振分析，我们发现Dapa与钠氢交换体1（NHE1）直接结合。功能获得和丧失实验进一步证明了NHE1在Dapa保护作用中的作用。在高脂饮食喂养5个月的小鼠中进行体内实验。在最后2个月给小鼠腹腔注射Dapa（1 mg·kg·d）。给予Dapa显著降低了体重并改善了血脂谱。给予Dapa还通过抑制MAPK/AP-1途径和减轻心脏炎症，缓解了高脂饮食诱导的心脏功能障碍和心脏异常重塑。总之，除了降低血脂的作用外，Dapa对饱和脂肪酸诱导的心肌细胞损伤具有直接保护作用。这种保护作用是通过以NHE1依赖的方式负调节MAPK/AP-1途径实现的。本研究突出了Dapa在预防肥胖相关性心脏功能障碍方面临床应用的潜力。
