Abstract
The molecular and cellular mechanisms that link cardiovascular risk factors to the initiation and progression of atherosclerosis are not understood. Recent findings from our laboratory indicate that endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3α/β induces pro-atherosclerotic pathways. The objective of this study was to define the specific roles of GSK3α and GSK3β in the activation of pro-atherogenic processes in macrophages. Bone marrow derived macrophages (BMDM) were isolated from low-density lipoprotein receptor knockout (Ldlr-/-) mice and Ldlr-/- mice with myeloid deficiency of GSK3α and/or GSK3β. M1 and M2 macrophages were used to examine functions relevant to the development of atherosclerosis, including polarization, inflammatory response, cell viability, lipid accumulation, migration, and metabolism. GSK3α deficiency impairs M1 macrophage polarization, and reduces the inflammatory response and lipid accumulation, but increases macrophage mobility/migration. GSK3β deficiency promotes M1 macrophage polarization, which further increases the inflammatory response and lipid accumulation, but decreases macrophage migration. Macrophages deficient in both GSK3α and GSK3β exhibit increased cell viability, proliferation, and metabolism. These studies begin to delineate the specific roles of GSK3α and GSK3β in macrophage polarization and function. These data suggest that myeloid cell GSK3α signaling regulates M1 macrophage polarization and pro-atherogenic functions to promote atherosclerosis development.
Highlights
Cardiovascular disease (CVD) is the leading cause of death in the world today [1] and atherosclerosis is a major underlying cause of CVD
Subsets of Bone marrow derived macrophages (BMDM) were exposed to 10 ng/ml LPS or 10 ng/ml IL-4 for 24 hrs to polarized them to M1 and M2, respectively
LMbKO and LMabKO macrophages showed decreased expression of IL12p70 and KC compared to Labfl/fl (Figure 3E). Together these results suggest that GSK3a deficiency impairs the pro-inflammatory response and GSK3b deficiency enhances the pro-inflammatory response of M1 macrophages
Summary
Cardiovascular disease (CVD) is the leading cause of death in the world today [1] and atherosclerosis is a major underlying cause of CVD. Monocytes invade the subintima and differentiate into macrophages. These macrophages take up modified-LDL particles and become foam cells, which form fatty streaks in the artery wall. Macrophage/foam cell apoptosis leads to the establishment of a necrotic core, which is a key feature of unstable plaques that are prone to rupture. Lesion rupture triggers atherothrombosis and can occlude the artery. This can lead to acute cardiovascular complications (myocardial infarction or stroke) and potentially death. The underlying molecular mechanisms that regulate macrophage function during the development of atherosclerosis are not completely understood
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