Activated alpha2 Macroglobulin induces GLUT4 traffic to cell surface through LRP1 in cardiomyocytes

ACTIS DATO VIRGINIA; CHIABRANDO, GUSTAVO A

Salta

Congreso; Joint XIV PABMB congress and LV annual SAIB meeting; 2019

Diabetes mellitus (DM) is a highly incidence chronic disease that affect global health. Cardiovascular complications include myocardial infarction, which are the major cause of death in diabetic patients. 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. A high level of activated α2-macroglobulin (α2M*) has been found in circulation in patients with DM in a large cohort. α2M* is a proteinase-inhibitors complex that is specifically recognised and internalized by endocytosis through LRP1 (for low density lipoprotein receptor-related protein 1). LRP1 is an endocytic and signalling receptor highly expressed in cardiomyocytes. This receptor is stored in vesicles, which can be sorted to plasma membrane (PM) by insulin and α2M* through a regulated exocytic route. The most of these vesicles also contain GLUT4 (for glucose transporter type 4) which is the main insulin-sensitive glucose transporter in the myocardium. We hypothesize that α2M* promotes the GLUT4 intracellular traffic to PM in HL1-1 cardiomyocytes cell line. By Western blot we found that α2M* activated the PI3K/Akt and MAPK/ERK pathways in HL-1 cells. Finally, by biotinylation and in cell Western blot assays we found that α2M* increased the GLUT4 and LRP1 expression on the cell surface. These results may have physiopathological implications related to glucose homeostasis in cardiomyocytes.