Investigating the Role of Glycogen Synthase Kinase-3α in the Initiation and Progression of Atherosclerosis

Abstract

<p>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 of advanced plaque formation. Furthermore, hepatic and vascular ER stress levels were unaffected by the deletion of GSK-3α, a result that is consistent with the hypothesis that GSK-3α functions downstream of ER stress. Macrophages isolated from GSK-3α deficient mice had a reduction in unesterified cholesterol accumulation as well as a significant increase in the expression of the anti-inflammatory cytokine IL-10. Finally, BMT experiments showed a significant decrease in plaque size in the aortic sinus of LDLR^-/-GSK-3α^+/+ mice transplanted with GSK-3α deficient bone marrow. These results demonstrate a possible link between ER stress-induced activation of GSK-3α and the downstream effects leading to atherogenic initiation and progression.</p>