Abstract
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 in vitro studies. Mechanistically, we found that GDL treatment was strongly associated with activation of pro-survival extracellular signal-regulated kinase (ERK) signaling both in vivo and in vitro, and pharmacological inhibition of ERK signaling via 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 via activation of ERK signaling.
Highlights
Gluconolactone (D-glucono-1,5-lactone or GDL) is a polyhydroxy acid (PHA), a lactone or oxidized derivative of glucose, and is widely distributed in nature ranging from bacteria to humans
Our results demonstrated that GDL exerted cardioprotection against I/R injury, partly due to the activation of its potential target Protein kinase C (PKC) and downstream prosurvival extracellular signal-regulated kinase (ERK) signaling
In this study, using a mouse model of I/R injury and a cellular model of H/R mimicking this process, we revealed that GDL administration (5 mg/kg, i.p.) attenuated I/R injury and reperfusion-induced
Summary
Gluconolactone (D-glucono-1,5-lactone or GDL) is a polyhydroxy acid (PHA), a lactone or oxidized derivative of glucose, and is widely distributed in nature ranging from bacteria to humans. GDL can be naturally found in honey, grapes and fruit juices, and widely used in dietary products such as yogurt, cheese, bread, wine and tofu, etc., as a food additive (European food additive number E575). GDL as a human natural metabolite has attracted more and more attention, and its levels were shown to change significantly under different pathophysiological conditions. Zhao et al (2018) demonstrated that fecal GDL increased about twofold in normal human subjects after half-marathon race compared with those before race. Makowski et al (2014) showed that threefold decrease of GDL were observed in tumors from obese mice compared with lean counterparts. The role of GDL in the development of cardiovascular diseases remains elusive
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