Abstract 441: Cigarette Smoke Regulation of Cholesterol Efflux and Protease Production in Atherosclerosis Decreases Plaque Collagen Content and Increases Plaque Necrosis
There is strong epidemiological data linking smoking to an increase in the incidence and severity of cardiovascular diseases. However, the molecular mechanisms responsible for this susceptibility are unknown. Recent studies report progression of atherosclerosis with smoke exposed individuals developing a higher incidence of acute coronary events. We investigated the influence of cigarette smoke exposure on the development of atherosclerotic lesions in apolipoprotein E (Apoe) knockout mice and demonstrated an increase in lesion size along with cholesterol levels in Apoe knockout mice exposed to cigarette smoke for 20 weeks. In addition, there was a dramatic increase in plaque necrosis with a decrease in the collagen content of lesions. The accumulation of lipids in macrophages induces an inflammatory response, with the secretion of cytokines and proteases, and leads to apoptosis and necrosis within the lesion. Our hypothesis is that cigarette smoke components impair cholesterol efflux and increase MMP expression in macrophages, leading to increased apoptosis and necrosis. Whole cigarette smoke extract (5% CSE) significantly impaired cholesterol efflux to ApoAI in elicited peritoneal macrophages correlating with the down regulation of ABCA1 and ABCG1 transporters. In addition, 5% CSE induced expression of several crucial matrix metalloproteinases in human THP-1 macrophages (MMP-1, 8, 13, 14) and mouse peritoneal macrophages (MMP-9, 13). After increasing ABCA1 and G1 expression with treatment with an LXR agonist the CSE-induced up regulation of MMPs (MMP-9 and 13) was inhibited suggesting a correlation between the loss of ABC transporters and MMP expression. Ex vivo experiments utilizing peritoneal macrophages elicited from mice exposed to cigarette smoke for 4 days demonstrated a decrease in ABCA1 and ABCG1 expression with the up regulation of MMPs (MMP-9, 12, 13 and 14) confirming that parallel to impairing cholesterol efflux through the down regulation of ABC transporters, cigarette smoke components induce MMPs ex vivo. The combined effect of cigarette smoke on protease expression and cholesterol efflux are likely synergistic in generating a more vulnerable plaque through an increase in necrosis and a lower collagen content whereby the mechanism is secondary to a direct effect of cigarette smoke on the expression of ABC transporters.
- © 2012 by American Heart Association, Inc.