The impact of geranylgeranyltransferase type I (GGTase-I) deficiency in macrophages on the pathogenesis and development of inflammation related disorders

Examensarbete för masterexamen
Master Thesis
Alexandersson, Ellen M
Cardiovascular diseases are the leading cause of death in the industrial countries and the most common underlying pathology is atherosclerosis. Major risk factors of atherosclerosis are hypertension, diabetes, smoking, free radicals and high levels of cholesterol in the blood. The high cholesterol concentrations often leas to lipid deposits at the inner surface of coronary arteries that triggers an inflammatory process with the results of lipid cores and narrowing of the arteries. The mechanisms behind atherosclerosis are not yet fully understood and therefore it is important to focus on understanding the cellular processes and underlying mechanisms of the disease. Statins are a group of cholesterol lowering drugs that target the cholesterol pathway by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase. Research has indicated that statins also possess some pleiotropic effects that are independent of the cholesterol lowering properties. It is thought that the pleiotropic effects are connected to statins ability to block the synthesis of the isoprenoid intermediates geranylgeranyl-pyrophosphate and farnesylpyrophosphate, which are used by gernylgeranyltransferase typ I (GGTase-I) and farnesyltransferase (FTase) in post-translational modifications of CAAX-proteins. The aim of this thesis was to define the impact of GGTase-I deficiency in macrophages and connect the findings to the pathogenesis of atherosclerosis. In this study it is shown that GGTase-I dficiency has striking effects on the progression of lipid lesions in the aortas of mice, with a reduction of around seventy percentage in males. The blood lipids were not altered, which point at that the positive effects do not depend on a decrease of cholesterol in the blood. Expression of scavenger receptors Sr-A1, Sr-B1, Cd36 and Marco were reduced and a decrease in cytokine Interleukin 10 was also demonstrated. It was further shown that treatment with lipopolysaccharides caused a stronger upregulation of scavenger receptors in the knockout cells compared to the controls, which indicates that these cells are more sensitive for inflammatory stimulation. The overall conclusion is that GGTase-I deficiency is strongly connected to the atherosclerotic process in mice, but the research in this area needs to continue to connect these findings in a broader perspective.
Livsvetenskaper , Industriell bioteknik , Life Science , Industrial Biotechnology
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