GCN5L1 regulates glucose and ketone body metabolism during cardiac ischemia-reperfusion injury

Abstract

Ischemic heart diseases are the leading cause of death among cardiovascular diseases. Reperfusion of the ischemic myocardium is the only way to treat IHD. However, reperfusion can damage the ischemic myocardium if it does not happen at the right time. Therefore, understanding the pathophysiology of cardiac ischemic reperfusion injury is essential to identifying new therapeutic targets. We reported the cardioprotective role of GCN5L1 in ex-vivo cardiac ischemic reperfusion injury through the regulation of cytoprotective signaling by reducing oxidative stress. The current study investigated the role of GCN5L1 in in-vivo cardiac ischemic reperfusion injury and in-vitro H/R injury in AC16 cells. The cardiac-specific GCN5L1 KO did not further deteriorate the cardiac function and infarct size. We measured the glucose metabolism-related protein expression among all experimental groups and found that GCN5L1 KO significantly decreases glucose metabolism by PDH phosphorylation. We further evaluated the role of GCN5L1 in in-vitro H/R injury in genetically modified AC16 cells (GCN5L1 KD and overexpressed and control). GCN5L1 KD in AC16 cells promotes phosphorylation of PDH; similarly, overexpression reduces the p-PDH levels. We identified that the regulation of PDH phosphorylation via PDK4/PDP1/PDPR and GCN5L1 regulates the PDK4 expression. We measured the ketone body metabolism related to protein expression in control and KD cells after H/R injury and found the upregulation of ketone body metabolism-related protein expression in KD cells compared to control AC16 cells. Altogether, our in vivo and in vitro studies findings conclude that GCN5L1 is required for glucose metabolism in ischemic reperfusion injury, and in the absence of GCN5L1, ketone body metabolism accomplishes the cardiac energy requirements and prevents I/R induced cardiac damage and infarct size.Graphical AbstractGraphical abstract of the manuscriptAltogether, our results conclude that Cardiomyocyte-specific GCN5L1 KO in-vivo cardiac ischemic reperfusion injury and in-vitro Hypoxia-reoxygenation stress significantly affect glucose metabolism by suppressing glucose metabolism. Cardiac-specific GCN5L1 KO mice in-vivo and knockdown in AC16 cells invitro upregulates the expression of enzymes that are involved in the ketone body metabolism to rescue from in-vivo cardiac ischemic reperfusion injury and invitro H/R stress.