Yanliang Yuan1, Xiucheng Liu1, Haoran Miao1, Bing Huang1, Zhiwei Liu2, Jiali Chen1, Xiaoyu Quan1, Lidong Zhu1, Hongyan Dong3, Zhongming Zhang4. 1. Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou 221006, Jiangsu, China. 2. Morphological Research Experiment Center, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China. 3. Morphological Research Experiment Center, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China. Electronic address: dhy@xzhmu.edu.cn. 4. Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou 221006, Jiangsu, China.. Electronic address: zhang_zhongming@xzhmu.edu.cn.
Abstract
BACKGROUND: Targeted increase in glucose uptake of ischemic myocardium is a potential therapeutic strategy for myocardial ischemia. PEDF presents a profound moderating effect on glucose metabolism of cells, but its role is still controversial. Here, we try to demonstrate the direct effect of PEDF on glucose uptake in ischemic myocyte and to elucidate its underlying mechanism. METHODS AND RESULTS: Lentivirus vectors carrying PEDF gene were delivered into the myocardium to locally overexpress PEDF in a myocardial ischemia/reperfusion rat model. PET imaging showed that PEDF local overexpression increased [18F]-FDG uptake of ischemic myocardium. In vitro, PEDF directly increased the glucose uptake in hypoxic cardiomyocytes. The expression of glucose transporter 4 (GLUT4) on plasma membrane of hypoxic cardiomyocytes was significantly upregulated by PEDF, but its total amount was not changed. The increased glucose uptake and cardioprotective effects induced by PEDF were blocked by the GLUT4 inhibitor indinavir. PEDF-mediated GLUT4 translocation and glucose uptake increase in hypoxic cardiomyocytes were prevented by phosphatidyl-inositol-3 kinase (PI3K) inhibitor or AKT inhibitor. The PEDF-mediated glucose uptake was also diminished when PEDF receptor (PEDFR) was downregulated or potent phospholipase A2 enzymatic activity was inhibited. CONCLUSIONS: PEDF can increase glucose uptake in ischemic myocardium through a PEDFR-dependent mechanism, involving PI3K/AKT signaling and GLUT4 translocation.
BACKGROUND: Targeted increase in glucose uptake of ischemic myocardium is a potential therapeutic strategy for myocardial ischemia. PEDF presents a profound moderating effect on glucose metabolism of cells, but its role is still controversial. Here, we try to demonstrate the direct effect of PEDF on glucose uptake in ischemic myocyte and to elucidate its underlying mechanism. METHODS AND RESULTS: Lentivirus vectors carrying PEDF gene were delivered into the myocardium to locally overexpress PEDF in a myocardial ischemia/reperfusion rat model. PET imaging showed that PEDF local overexpression increased [18F]-FDG uptake of ischemic myocardium. In vitro, PEDF directly increased the glucose uptake in hypoxic cardiomyocytes. The expression of glucose transporter 4 (GLUT4) on plasma membrane of hypoxic cardiomyocytes was significantly upregulated by PEDF, but its total amount was not changed. The increased glucose uptake and cardioprotective effects induced by PEDF were blocked by the GLUT4 inhibitor indinavir. PEDF-mediated GLUT4 translocation and glucose uptake increase in hypoxic cardiomyocytes were prevented by phosphatidyl-inositol-3 kinase (PI3K) inhibitor or AKT inhibitor. The PEDF-mediated glucose uptake was also diminished when PEDF receptor (PEDFR) was downregulated or potent phospholipase A2 enzymatic activity was inhibited. CONCLUSIONS:PEDF can increase glucose uptake in ischemic myocardium through a PEDFR-dependent mechanism, involving PI3K/AKT signaling and GLUT4 translocation.