Inflamació i aterosclerosi
Atherosclerosis, the main cause of coronary artery disease (CAD), is an inflammatory disease.
It is commonly accepted that chronic inflammation, as observed in periodontal disease,
lupus erythematosus, rheumatoid arthritis, or chronic bronchitis, contributes to higher mortality and morbidity from cardiovascular disease. However, experiments are needed to ascertain the long-term effects of chronic inflammation and the effect of anti-inflammatory agents on
the development and progression of atherosclerosis. It has been suggested that the use of antiinflamatory drugs could offer new opportunities for the prevention and treatment of CAD.
Previous studies indicate the efficacy of aspirin and other antiplatelet drugs in reducing the risk of a serious vascular event, such as nonfatal myocardial infarction, nonfatal stroke or death from vascular diseases. These effects have been demonstrated using low-dose aspirin resulting in the permanent inactivation of a key platelet enzyme, cyclooxygenase 1 (COX-1) that mainly catalyzes the conversion of arachidonic acid into tromboxane A2 (TXA2), resulting in lower levels of TXA2, thus inhibits platelet aggregation. Higher levels of aspirin are needed to inhibit COX-2 than to inhibit COX-1. Vascular prostacyclin (PGI2) is derived predominantly from COX-2 and is less susceptible to inhibition by low doses of aspirin.
Previous studies have shown that short-term administration of high doses of aspirin reduces the atherosclerotic lesion size in apolipoprotein E-deficient mice. However, to date it has not been studied the effect of long-term administration of high doses of aspirin in the apolipoprotein E-deficient mice.
The results presented in this thesis show that long-term administration of high doses of aspirin does not attenuate the progression of atheosclerosis in apolipoprotein E-deficient mice. Moreover, the extent of atherosclerosis was significantly correlated with plasma cholesterol concentrations in our animal model, suggesting that apparently, the continous administration of aspirin was facilitating atherogenesis. However, we hypothesized that this effect was not produced by the administration of aspirin per se. It may be produced by any factor present in our model which was affecting our results. We especulate that a high-fat, high-cholesterol diet could be a complicating factor. This was further exemplified by the results from study 2, which indicate that mice given high fat/high cholesterol diets developed an impairment of liver histology consisting of fat accumulation, macrophage proliferation, and inflammation. We also found a chronological and quantitative relationship between liver impairment and the formation of atheromatous lesions, indicating that feeding these mice with high-fat/cholesterol diets could be a complicating factor. Our findings, also suggest that apo E-KO mice may provide an experimental model for the effect of Western diet on the development of steatohepatitis.
Finally, we have found that a repeated injection of turpentine over such a protracted
period of time, which was not modified by the use of aspirin, closely resembled the characteristic pattern of inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. In mice with turpentine-induced inflammation, the plasma cholesterol levels, atherosclerotic lesions and the hepatic expression of the multiple- drug resistance gene (mdr1b) were lower than in controls. We suggest that mdr1b could play an important role in regulation of plasma cholesterol and/or the progression of atherosclerosis.
Advisor:Joven Maried, Jorge
School:Universitat Rovira i Virgili
Source Type:Master's Thesis
Keywords:departament de bioquímica i biotecnologia
Date of Publication:01/18/2006