GLYCOGEN SYNTHASE KINASE-3α IN THE DEVELOPMENT OF ATHEROSCLEROSIS INVESTIGATING THE ROLE OF GLYCOGEN SYNTHASE KINASE-3α IN THE INITIATION AND PROGRESSION OF ATHEROSCLEROSIS

Atherosclerosis is a chronic inflammatory disease of the arterial wall and is the primary cause of coronary artery disease, the most common cause of death in western societies. Risk factors for cardiovascular disease include dyslipidemia, diabetes, smoking, and obesity. These risk factors have also been shown to promote vascular endoplasmic reticulum (ER) stress; a cellular response characterized by the accumulation of misfolded proteins in the ER. Thickening and decreased stability of arterial plaque can lead to thrombosis and subsequent clinical complications of myocardial infarction and stroke. However, the exact mechanisms that lead to the development of atherosclerosis remain unclear. Here we show that inhibition, as well as a deficiency of glycogen synthase kinase (GSK)-3α, can protect against accelerated atherosclerosis in a low-density lipoprotein receptor (LDLR) knockout mouse model. Compared to LDLR-/- controls, mice deficient in GSK-3α showed a decrease in lesion volume in the aortic root as well as protection against diet-induced hepatic steatosis. In addition, necrotic core volume was significantly reduced in LDLR-/-GSK-3α-/- mice compared to controls, a characteristic indicative o