Nicotine induced changes in gene expression by human coronary artery endothelial cells
Introduction
Cigarette smoking is a major risk factor for coronary heart disease (CHD), with age-adjusted hazard ratios for death from CHD being 2.5 for man and 3.2 for woman [1], [2]. Although the underlying mechanisms are not completely understood, there is substantial evidence indicating that the primary role of cigarette smoking in CHD is to cause injury to the vascular endothelium by direct cytotoxicity, leading to endothelial cell dysfunction and initiating the pathogenesis of coronary atherosclerosis, the primary vascular lesion of CHD [3], [4], [5].
The normal vascular endothelium possesses a number of important physiological properties that retard the development of atherosclerosis. According to the widely accepted ‘Response to injury hypothesis’ [3], [6], atherogenesis is initiated by chemical (such as tobacco smoke and hyperlipidaemia), biological (such as chlamydia pneumoniae infection) and/or mechanical (such as increased shear stress in hypertension) insults to endothelial cells. This can result in endothelial dysfunction characterized by the loss of the homeostatic mechanisms operative in healthy endothelial cells [3], [7]. Major manifestations of endothelial dysfunction include altered vasoreactivity, enhanced permeability to plasma lipoproteins, hyper-adhesivity for mononuclear leukocytes, and increased thrombogenicity, all of which are important mechanisms in the pathogenesis of atherosclerosis. It appears that these phenotypic changes of endothelial cells are associated with altered expression of genes encoding various pro- or anti-thrombotic factors, vaso-relaxors or constrictors, growth inhibitors or stimulators, and anti- or pro-inflammatory factors. Evidence from studies of smokers and/or cultured endothelial cells (originated from blood vessels other than coronary arteries) suggests that such factors may include von Willebrand factor (vWF) [8], [9], [10], [11], [12], endothelin-1 (ET-1) [13], [14], [15], tissue-type plasminogen activator (tPA) [16], plasminogen activator inhibitor-1 (PAI-1) [17], angiotensin-1 converting enzyme (ACE) [18], [19], and basic fibroblast growth factor [20]. It is possible that vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (ELAM-1) and endothelial nitric oxide synthase (eNOS), may also be involved, although reported data have been conflicting [21], [22], [23], [24], [25], [26].
In this study, we investigated the response of human coronary artery endothelial cells to exposure to nicotine, the major active component of cigarette smoke [1], by screening the expression of a panel of endothelial genes that have been implicated in atherogenesis. The results showed that nicotine at concentrations found in the plasma/serum of smokers altered the expression of vWF, PAI-1, tPA, eNOS, ACE, and VCAM-1 in these cells. To our knowledge, this is the first study examining the effects of nicotine on gene expression systematically and also the first study addressing such effects in human coronary artery endothelial cells.
Section snippets
Primary human coronary artery endothelial cell culture
Primary human coronary artery endothelial cells (HCAEC) were purchased from Cell Applications Incorporation (San Diego, CA, USA). The cells were originally isolated from normal human coronary arteries and had been shown to express factor VIII-related antigen, a marker of endothelial cells. In this study, HCAEC cells were cultured in an endothelial cell growth medium (Cell Applications, San Diego, CA, USA), which was supplemented with trace elements, growth factors and antibiotics. The cells
Results
The expression of a total of ten genes in human coronary artery endothelial cells treated or untreated with nicotine at either 10−5 or 10−7 M concentration was studied. They were vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (ELAM-1), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF), endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), angiotensin-1 converting enzyme (ACE), basic
Discussion
Vascular endothelial dysfunction is recognized as an initial step in atherogenesis [3], [7]. Cigarette smoking can cause vascular endothelial dysfunction by promoting endothelial cell damage [4], [5]. In the present study, we have detected altered gene expressions in HCAEC cells induced by nicotine at concentrations equivalent to those found in cigarette smokers [27], [28]. Previous studies have shown that initial injurious events of endothelium in atherogenesis do not necessarily lead to
Acknowledgements
This work was supported by the British Heart Foundation (PG/98192 and PG/98183).
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