A Soluble Receptor for Advanced Glycation End‐Products Attenuates Myocardial Ischemia/Reperfusion Injury via Enhancing Glucose Metabolism

Glucose transporter 4 (GLUT4)-mediated glucose metabolism is a promising therapeutic target facilitating cardiomyocyte survival during myocardial ischemia/reperfusion (I/R) injury. Soluble receptor for advanced glycation end-products (sRAGE) has been proven to attenuate I/R injury via inhibiting AGE-RAGE mediated signaling pathways, but its role in regulating glucose metabolism remains unclear. Recently, AGEs were reported to hamper the GLUT4 translocation by interfering with the insulin signaling pathway in granulosa cells. Thus, it was speculated that sRAGE might inhibit myocardial I/R injury by enhancing the GLUT4-mediated glucose metabolism. Cardiomyocyte-specific sRAGE knock-in mice were constructed and underwent I/R surgery. H9c2 cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R). The overexpression of sRAGE in cardiomyocytes improved cardiac function, decreased infarct size, and inhibited apoptosis during myocardial I/R injury. sRAGE did not affect the expression of total GLUT4 but increased the translocation of GLUT4 to the plasma membrane, which enhanced the glucose uptake in cardiomyocytes. Meanwhile, sRAGE increased the production of lactate, NADH/NAD⁺, and adenosine triphosphate levels in cardiomyocytes during OGD/R. sRAGE activated the AMP-activated protein kinase (AMPK)/Akt substrate of 160 kDa (AS160) signaling pathway, and the application of AMPK inhibitor or AS160 mutant abolished the effect of sRAGE on facilitating plasma membrane GLUT4 localization and glucose metabolism. Moreover, the AMPK inhibitor or silenced GLUT4 depleted the anti-apoptotic effect of sRAGE during OGD/R in cardiomyocytes. Therefore, it was suggested that sRAGE inhibited I/R-induced apoptosis via enhancing the GLUT4 translocation to the plasma membrane and glucose metabolism through the AMPK/AS160 signaling pathway.