Qin Xinghua, Liu Binghua, Gao Feng, Hu Yuanyuan, Chen Ziwei, Xu Jie, Zhang Xing
School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.
Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, China.
Front Physiol. 2022 Mar 14;13:856699. doi: 10.3389/fphys.2022.856699. eCollection 2022.
Gluconolactone (D-glucono-1,5-lactone or GDL) is a food additive which presents in dietary products such as tofu, yogurt, cheese, bread, wine, etc. GDL has long been considered as a free radical scavenger; however, its role in cardioprotection remains elusive. In this study, using a mouse model of myocardial ischemia/reperfusion (I/R) injury and a model of hypoxia/reoxygenation (H/R) in neonatal rat cardiomyocytes (NRCM), we explored the role of GDL in I/R injury. We found that GDL (5 mg/kg, i.p.) attenuated myocardial I/R injury as evidenced by decreased infarct size, release of cardiac injury markers and apoptosis. Additionally, GDL decreased reperfusion-induced arrhythmias and oxidative stress. These effects were also observed in parallel studies. Mechanistically, we found that GDL treatment was strongly associated with activation of pro-survival extracellular signal-regulated kinase (ERK) signaling both and , and pharmacological inhibition of ERK signaling U0126 attenuated GDL-induced cardioprotection against H/R injury in NRCM cells. To reveal how GDL regulates ERK signaling, we predicted the putative targets of GDL by Swiss Target Prediction, and protein kinase C (PKC) emerged as the most promising target for GDL. By pharmacological intervention and immunofluorescence, we found that PKCε, an important member of the PKC family, was activated after GDL treatment in heart, thereby leading to ERK activation and cardioprotection against I/R injury. Taken together, our results demonstrated that GDL acts as a potent activator of PKCε and, thus, provides cardioprotection against I/R injury activation of ERK signaling.
葡萄糖酸内酯（D-葡萄糖酸-1,5-内酯或GDL）是一种食品添加剂，存在于豆腐、酸奶、奶酪、面包、葡萄酒等食品中。长期以来，GDL一直被认为是一种自由基清除剂；然而，其在心脏保护中的作用仍不明确。在本研究中，我们使用心肌缺血/再灌注（I/R）损伤的小鼠模型和新生大鼠心肌细胞（NRCM）的缺氧/复氧（H/R）模型，探讨了GDL在I/R损伤中的作用。我们发现，GDL（5mg/kg，腹腔注射）减轻了心肌I/R损伤，表现为梗死面积减小、心脏损伤标志物释放减少和细胞凋亡减少。此外，GDL减少了再灌注诱导的心律失常和氧化应激。在平行研究中也观察到了这些效应。机制上，我们发现GDL治疗与促生存的细胞外信号调节激酶（ERK）信号通路的激活密切相关，并且ERK信号通路的药理学抑制剂U0126减弱了GDL诱导的对NRCM细胞H/R损伤的心脏保护作用。为了揭示GDL如何调节ERK信号通路，我们通过瑞士靶点预测软件预测了GDL的潜在靶点，蛋白激酶C（PKC）成为GDL最有希望的靶点。通过药理学干预和免疫荧光，我们发现PKC家族的重要成员PKCε在心脏接受GDL治疗后被激活，从而导致ERK激活并对I/R损伤起到心脏保护作用。综上所述，我们的结果表明，GDL作为PKCε的有效激活剂，通过激活ERK信号通路提供对I/R损伤的心脏保护作用。
