Objective. Collagen plays a major role in arterial wall remodeling, aneurysm formation, and atherosclerotic cap stability. Smokers often have weakened arterial walls associating with aneurysm and thinned atherosclerotic plaque caps leading to rupture and acute coronary syndromes. We hypothesize that these detrimental effects on arterial wall by tobacco are partially mediated by disturbed collagen metabolism. Methods and results. We first investigated the effect of cigarette smoke extracts (CSE) on prolyl-4-hydroxylase (P4H) expression and collagen production in human aortic endothelial cells (HAECs) and human coronary artery smooth muscle cells (HCSMCs). After exposure to 0.01-U CSE for 24 h, expression of P4Halpha-a rate limiting subunit of P4H enzyme responsible for the formation of 4-hydroxyproline in mature functional collagen, was significantly down-regulated according to Western blotting and quantitative RT-PCR (HAEC p < 0.01 and HCSMC p < 0.001) when treated by CSE. The decreased P4Halpha expression was corresponded with reduced cellular collagen levels (HAEC p < 0.001 and HCSMC p < 0.001). We also found that one of the cigarette components benzo(a)pyrene exerted similar effect as CSE, but not nicotine or acrolein. We further examined P4H expression in a few human atherosclerotic abdominal aortas. These in vivo data demonstrated that smokers had thinner atherosclerotic cap thickness and lower levels of P4Halpha and collagen. Conclusions. Our study suggests that cigarette may interfere with one of the key enzymes in arterial wall collagen metabolism, which may be responsible for thin fibrous cap in atherosclerotic lesion, impaired arterial wall extensibility, and increased likelihood of aneurysm in smokers. (C) 2004 Elsevier Inc. All rights reserved.