ACTIVATED ALPHA-2 MACROGLOBULIN INDUCES THE GLUT4 TRAFFIC TO CELL SURFACE THROUGH LRP1 IN CARDIOMYOCYTES

CHIABRANDO GA; ACTIS DATO V

Congreso; LV Reunion Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2019

SAIB

Diabetes mellitus (DM) is a highly-incidence chronic disease that affects global health. The major cause of death in diabetic patients is produced by cardiovascular complications, which include myocardial infarction. The heart requires an enormous amount of energy for its daily function and the insulin-induced glucose uptake represents approximately 30% of the energy source available for this tissue. In this way, insulin resistance has a marked influence on cardiac metabolism because the action of insulin in the myocardium is affected, the contribution of substrates is altered and there are drawbacks in the metabolic adaptations in this organ. In addition, activated α2-macroglobulin (α2M*) is involved in cardiac hypertrophy of diabetic patients. α2M* is a proteinase-inhibitor complex that is specifically recognized and internalized by endocytosis through low-density lipoprotein receptor-related protein 1 (LRP1), which is an endocytic and signaling receptor expressed in cardiomyocytes. This receptor is stored in vesicles and sorted to the plasma membrane (PM) by insulin and α2M* through a regulated exocytic route. These vesicles also contain glucose transporter type 4 (GLUT4), which is the main insulin-sensitive glucose transporter in the myocardium. In the present work, we investigate whether α2M* may promote the GLUT4 intracellular traffic to PM in cardiomyocytes mimicking the insulin function. The experiments were performed in cell cultures of mouse cardiomyocyte cell line, HL-1. Several cellular and molecular tools were applied in order to evaluate intracellular signaling activation and membrane protein trafficking in HL-1 cells stimulated for different times with α2M* (60 nM). Our results demonstrate that α2M* promoted a rapid and significant activation of the PI3K/Akt pathway as well as increased expression of GLUT4 and LRP1 on the cell surface in HL-1 cells. This intracellular signaling activation and GLUT4 sorting to the PM was comparable to those induced by insulin (100 nM for 30 min). In conclusion, these results taken together may have pathophysiological implications on the extracellular regulation of glucose in cardiomyocytes.