Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China.
Int Immunopharmacol. 2023 Dec;125(Pt A):111038. doi: 10.1016/j.intimp.2023.111038. Epub 2023 Oct 29.
Oxidative stress is an essential component participating in the development and maintenance of atrial fibrillation (AF). Dapagliflozin, a SGLT2 inhibitor, has been shown to exert cardioprotective effects by ameliorating oxidative stress in multiple heart disease models. However, its potential to attenuate lipopolysaccharide (LPS)-induced myocardial injury in rats remains unknown.
This study aims to investigate the role of dapagliflozin in LPS-induced myocardial injury and the potential mechanisms involved.
Rats were intraperitoneally administered LPS to induce sepsis-like condition. The intervention was conducted with intraperitoneal injection of dapagliflozin or saline 1 h in advance. The effects of dapagliflozin were detected by electrophysiological recordings, western blot, qPCR, ELISA, HE staining, immunohistochemistry and fluorescence. We further validated the mechanism in vitro using HL-1 cells.
Dapagliflozin significantly improved LPS-induced myocardial injury, reduced susceptibility to AF, and mitigated atrial tissue inflammatory cell infiltration and atrial myocyte apoptosis. These were correlated with the Nrf2/HO-1 signaling pathway, which subsequently reduced oxidative stress. Subsequently, we used a specific inhibitor of the Nrf2/HO-1 pathway in vitro, reversed the anti-oxidative stress effects of dapagliflozin on HL-1 cells, further confirming the Nrf2/HO-1 pathway's pivotal role in dapagliflozin-mediated cardioprotection.
Dapagliflozin ameliorated myocardial injury and susceptibility to AF induced by LPS through anti-oxidative stress, which relied on upregulation of the Nrf2/HO-1 pathway.
氧化应激是参与心房颤动（AF）发生和维持的重要因素。SGLT2 抑制剂达格列净已被证明通过改善多种心脏病模型中的氧化应激发挥心脏保护作用。然而，其在减轻大鼠脂多糖（LPS）诱导的心肌损伤中的潜力尚不清楚。
本研究旨在探讨达格列净在 LPS 诱导的心肌损伤中的作用及其潜在机制。
通过腹腔内注射 LPS 诱导大鼠脓毒症样状态。在 LPS 注射前 1 小时通过腹腔内注射达格列净或生理盐水进行干预。通过电生理记录、Western blot、qPCR、ELISA、HE 染色、免疫组织化学和荧光检测达格列净的作用。我们进一步在 HL-1 细胞中验证了该机制。
达格列净显著改善 LPS 诱导的心肌损伤，降低 AF 易感性，并减轻心房组织炎症细胞浸润和心房肌细胞凋亡。这与 Nrf2/HO-1 信号通路相关，该通路随后减轻了氧化应激。随后，我们在体外使用 Nrf2/HO-1 通路的特异性抑制剂，逆转了达格列净对 HL-1 细胞的抗氧化应激作用，进一步证实了 Nrf2/HO-1 通路在达格列净介导的心脏保护中的关键作用。
达格列净通过抗氧化应激改善 LPS 诱导的心肌损伤和 AF 易感性，这依赖于 Nrf2/HO-1 通路的上调。
