Abstract
Tobacco smoking and hemodynamic forces are key stimuli in the development of endothelial dysfunction and atherosclerosis. High laminar flow has an atheroprotective effect on the endothelium and leads to a reduced response of endothelial cells to cardiovascular risk factors compared to regions with disturbed or low laminar flow. We hypothesize that the atheroprotective effect of high laminar flow could delay the development of endothelial dysfunction caused by cigarette smoking. Primary human endothelial cells were stimulated with increasing dosages of aqueous cigarette smoke extract (CSEaq). CSEaq reduced cell viability in a dose-dependent manner. The main mediator of cellular adaption to oxidative stress, nuclear factor erythroid 2-related factor 2 (NRF2) and its target genes heme oxygenase (decycling) 1 (HMOX1) or NAD(P)H quinone dehydrogenase 1 (NQO1) were strongly increased by CSEaq in a dose-dependent manner. High laminar flow induced elongation of endothelial cells in the direction of flow, activated the AKT/eNOS pathway, increased eNOS expression, phosphorylation and NO release. These increases were inhibited by CSEaq. Pro-inflammatory adhesion molecules intercellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), selectin E (SELE) and chemokine (C-C motif) ligand 2 (CCL2/MCP-1) were increased by CSEaq. Low laminar flow induced VCAM1 and SELE compared to high laminar flow. High laminar flow improved endothelial wound healing. This protective effect was inhibited by CSEaq in a dose-dependent manner through the AKT/eNOS pathway. Low as well as high laminar flow decreased adhesion of monocytes to endothelial cells. Whereas, monocyte adhesion was increased by CSEaq under low laminar flow, this was not evident under high laminar flow.This study shows the activation of major atherosclerotic key parameters by CSEaq. Within this process, high laminar flow is likely to reduce the harmful effects of CSEaq to a certain degree. The identified molecular mechanisms might be useful for development of alternative therapy concepts.
Highlights
Tobacco smoking is one of the most important risk factors of atherosclerosis, as the underlying process of heart attack and stroke [1]
Treatment with 10% or higher dosages of CSEaq reduced endothelial cell viability in a dose-dependent manner compared to unstimulated controls
In order to elucidate the underlying molecular mechanisms of nuclear factor erythroid 2-related factor 2 (NRF2) signaling in more detail, we studied the impact of CSEaq on the NAD(P)H quinone dehydrogenase 1 (NQO1) promoter activity
Summary
Tobacco smoking is one of the most important risk factors of atherosclerosis, as the underlying process of heart attack and stroke [1]. Endothelial dysfunction is an early event in atherosclerosis and has prognostic value for future cardiovascular events It is characterized by an imbalance between vasodilation and vasoconstriction, a pro-inflammatory phenotype of the endothelial cells, increased adhesion of monocytes and reduced bioavailability of nitric oxide (NO) [2]. Low or disturbed blood flow has a pro-atherogenic effect on the endothelium at medium and large arteries, promoting differentiation of endothelial and smooth muscle cells into pro-inflammatory phenotypes [9–13]. In response to laminar flow, the release of vasoactive substances such as nitric oxide (NO), decreases permeability to plasma lipoproteins as well as the adhesion of leukocytes [17] These molecular changes in response to laminar flow reduce the susceptibility of endothelial cells to cardiovascular risk factors compared to disturbed flow conditions [18]. This leads to changes in gene expression of different cellular systems [20]
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