Study of the association of mitochondrial and endoplasmic reticulum membranes in macrophages in the context of hypercholesterolemia: possible relevance for atherosclerosis

Abstract

Atherosclerosis is the main cause of all cardiovascular diseases and related mortality. Elevated LDL-cholesterol in the plasma and local oxidative stress are early events in the atherogenesis process. Besides, macrophages recruited from the circulating blood monocytes and resident in the subendothelial space are key cells involved in the initiation and progression of atherosclerosis. Marked changes in the phenotype and function of macrophages occurs when they are exposed to inflammatory stimuli or oxidized LDL (oxLDL), including elevation of intracellular calcium and mitochondrial dysfunction. In this context, some structures named mitochondria associated membranes (MAM), transient sites of physical connection between mitochondria and endoplasmic reticulum (ER), may be related to calcium delivery to mitochondria in activated macrophages. In previous studies we demonstrated that hypercholesterolemic LDL receptor knockout mice (Ldlr -/-) present increased mitochondrial oxidative stress in several tissues compared with control animals. Thus, we hypothesized that cholesterol enriched macrophage membranes induces and/or stabilize MAM structures, increasing calcium ion flux to mitochondria, what is followed by organelle oxidative stress, membrane permeability transition and finally cell death. Consequently, these events may be relevant for the atherosclerosis progression. Therefore, in this work, we plan to develop a molecular tool to evaluate in vitro and in vivo whether MAM extension and stability in macrophages may be regulated by varying cholesterol concentrations as well as by drugs commonly used in the treatment of hypercholesterolemia. In addition, we plan to check whether MAM correlates with the severity of experimental atherosclerosis. (AU)