Abstract 9808: Deletion of Arrdc4 Enhances Myocardial Glucose Transport and Ameliorates Ischemic Injury

Abstract

Cardiomyocytes depend on glycolysis instead of oxidative phosphorylation during hypoxia and utilize glucose as a primary anaerobic energy source. Cardiac glucose transport is facilitated by the expression of glucose transporters (GLUT1 and GLUT4) on the cell surface. The arrestins are a family of proteins that regulate the signaling and trafficking of different receptors and transporters on the plasma membrane. As a scaffold protein, beta-arrestins mediate endocytosis and signal termination of beta-adrenergic receptors in cardiomyocytes. However, unlike the well-characterized beta-arrestins, the physiological roles of the related proteins termed alpha-arrestins remain largely unknown in the heart. In this study, we discovered for the first time that a member of alpha-arrestins, Arrestin Domain-Containing Protein 4 (Arrdc4), functions as a regulatory scaffold protein of GLUT1 and controls cardiac glucose metabolism. We found that Arrdc4 interacts with GLUT1 and promotes its endocytosis in cardiomyocytes. Interestingly, the cardiac expression of Arrdc4 is significantly upregulated by myocardial ischemia. Arrdc4 decreases cell surface expression of GLUT1 and suppresses glucose transport in the wild-type (WT) mouse heart. Then, we generated a novel Arrdc4 knockout (KO) mouse using CRISPR/Cas9 genome editing and characterized the effects of Arrdc4 in an animal model of myocardial infarction (MI) by coronary artery ligation in vivo. Surprisingly, Arrdc4-KO mice exhibit smaller infarct size, fewer apoptotic cells, and higher left ventricular (LV) fractional shortening, resulting in better post-MI survival than WT mice. Furthermore, using the Langendorff perfusion system, we found that Arrdc4-KO hearts augment cardiac glucose transport and preserve better LV mechanical function during anaerobic perfusion than WT hearts ex vivo. These results demonstrate that Arrdc4-KO cardiomyocytes coordinately maintain the optimal expression of GLUT1 on the cell surface, which leads to a metabolic rearrangement to secure energy homeostasis under oxygen- and nutrient-limited environments. In conclusion, we identified Arrdc4 as a new adaptor protein for GLUT1 in cardiomyocytes and a key player in cardiac metabolism in the ischemic heart.