Effects of ace and selective COX-2 inhibition on atherosclerosis and cardiovascular risk - relationship to gender.

摘要

Atherosclerosis is an inflammatory disease characterized by progressive deposition of plaque within arteries, specifically in areas of high velocity flow like the aortic arch. Risk factors for atherosclerosis include hypertension and hypercholesterolemia. Atherosclerotic lesions can cause thickening and decreased flexibility of the affected arteries and result in damage to the endothelium, putting an individual at risk for thrombus formation, which could lead to heart attacks and strokes. One treatment for atherosclerosis is angiotensin converting enzyme (ACE) inhibitors, but the mechanism by which ACE inhibitors work is incompletely understood. Using an atherosclerotic mouse model, the apolipoprotein E knockout mouse (ApoE KO), we showed that the ACE inhibitor captopril is effective in delaying the progression of late-stage atherosclerosis with just two weeks of treatment. The retardation of lesion progression was independent of serum cholesterol levels.;Additionally, we investigated the role cyclooxygenase-2 (COX-2) plays in atherosclerosis and in the beneficial effects of ACE inhibition. We show that aortic COX-2 expression is increased in our atherosclerotic ApoE KO mice, independent of ACE inhibitor administration. Expression of COX-2 was not different between gender-matched vehicle and ACE inhibitor-treated mice, suggesting that the beneficial effect of inhibiting ACE on lesion progression is not COX-2-dependent. Furthermore, COX-2 expression was significantly higher in male ApoE KO mice compared with female littermates.;Finally, evidence suggests that reproductive-aged females are at a lower risk for an adverse cardiovascular event compared with age-matched males. Using a sensitive assay to determine cardiovascular risk, we show that atherosclerotic, reproductive-aged male ApoE KO mice are more susceptible to a cardiovascular stress than their female littermates with similar percent lesion coverage, suggesting cardiovascular risk in this model is not dependent on percent lesion coverage. However, after administration of a selective COX-2 inhibitor, atherosclerotic, reproductive-aged female ApoE KO mice survived at levels similar to vehicle-treated, diet-matched male littermates, implicating COX-2 activity in the cardiovascular advantage afforded to females.;In conclusion, these findings show that ACE inhibition for two weeks is effective in delaying atherosclerotic lesion progression with no effect on serum cholesterol levels. This beneficial effect does not appear to be COX-2 dependent. Female atherosclerotic mice exhibit cardiovascular protection compared to male littermates, and although the mechanism for this protection was not completely determined in these studies, it appears to be COX-2 dependent.