Abstract
Activated alpha-2 Macroglobulin (α2M*) is specifically recognized by the cluster I/II of LRP1 (Low-density lipoprotein Receptor-related Protein-1). LRP1 is a scaffold protein for insulin receptor involved in the insulin-induced glucose transporter type 4 (GLUT4) translocation to plasma membrane and glucose uptake in different types of cells. Moreover, the cluster II of LRP1 plays a critical role in the internalization of atherogenic lipoproteins, such as aggregated Low-density Lipoproteins (aggLDL), promoting intracellular cholesteryl ester (CE) accumulation mainly in arterial intima and myocardium. The aggLDL uptake by LRP1 impairs GLUT4 traffic and the insulin response in cardiomyocytes. However, the link between CE accumulation, insulin action, and cardiac dysfunction are largely unknown. Here, we found that α2M* increased GLUT4 expression on cell surface by Rab4, Rab8A, and Rab10-mediated recycling through PI3K/Akt and MAPK/ERK signaling activation. Moreover, α2M* enhanced the insulin response increasing insulin-induced glucose uptake rate in the myocardium under normal conditions. On the other hand, α2M* blocked the intracellular CE accumulation, improved the insulin response and reduced cardiac damage in HL-1 cardiomyocytes exposed to aggLDL. In conclusion, α2M* by its agonist action on LRP1, counteracts the deleterious effects of aggLDL in cardiomyocytes, which may have therapeutic implications in cardiovascular diseases associated with hypercholesterolemia.
Highlights
It is well established that LRP1 acts as a scaffold protein for the insulin receptor (IR), It isiswell established that LRP1 a scaffold protein for signaling the insulin activation receptor (IR), which considered critical for acts the asintracellular insulin in which is considered critical for the intracellular insulin signaling activation cardiomycardiomyocytes, neurons, and hepatocytes [20,32,33]
With LRP1,Inenhanced thestudy insulin increasing mediated by its interaction with
Contrast, it has been demonstrated that aggregated Low-density Lipoproteins (aggLDL), through its binding to LRP1, induces it has been demonstrated that aggLDL, through its binding to LRP1, induces cholesteryl ester (CE) accuCE accumulation and impairs insulin-induced IR activation in this cell type [20]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Receptor-related Protein-1) [13,14] This α2 M-proteinase complex, termed activated α2 M or α2 M*, can regulate several cellular events such as cell proliferation and migration, through the activation of intracellular signalling pathways mediated by LRP1 [15]. A cardiac isoform of α2 M (c-α2 M) has been characterized in human and rats [16,17] This cα M induces hypertrophic cell growth in ventricular cardiomyocytes via ERK1/2 and PI3 K/Akt and improves cardiac cell function through its interaction with LRP1 [16,18,19]. In the present work we evaluate whether α2 M* via LRP1 improves the insulin-induced response in CE-loaded HL-1 cardiomyocytes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
