Citation:

Cardiovascular Research Supplements ( 2016 ) 111 ( S1 ), S104

Background/Introduction: Tobacco smoking and local hemodynamic forces are key stimuli in the development of endothelial dysfunction and atherosclerosis. High laminar flow has an atheroprotective effect on the endothelium. This leads to a reduced response of endothelial cells to cardiovascular risk factors compared to regions with disturbed or low laminar flow. The molecular mechanisms controlling the atheroprotective effect of high laminar flow and its effect on the cardiovascular risk factor of smoking is not well understood.

Purpose: We hypothesize that the atheroprotective molecular mechanisms of high laminar flow could be used to prevent the development of endothelial dysfunction by tobacco smoking. Therefore, we exposed human endothelial cells to cigarette smoke extract (CSEaq) under different flow conditions and studied gene expression, monocyte adhesion and wound healing.

Methods/Results: Primary human endothelial cells were stimulated with increasing dosages of CSEaq for 24-48h. CSEaq reduced cell viability in a dose-dependent manner. The main mediator of cellular adaption to oxidative stress NRF2 and its target genes heme oxygenase 1 and NAD(P)H dehydrogenase (quinone 1) 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 PKB/AKT pathway, followed by increased eNOS expression and subsequent NO release. This increase was inhibited by CSEaq in a time-dependent manner. Induction of the NRF2 system by CSEaq was not further regulated by high laminar flow. In contrast, proatherosclerotic low laminar flow had no effect on eNOS expression and NO release compared to high laminar flow. Proinflammatory adhesion molecules ICAM1, VCAM1, SELE, and CCL2 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. Low laminar flow did not affect wound healing compared to static conditions. Low and high laminar flow decreased adhesion of primary monocytes to endothelial cells. Interestingly, monocyte adhesion was increased by CSEaq under low laminar flow, which was not evident under high laminar flow.

Conclusions: In conclusion, our data suggest novel molecular mechanisms that underlie the association between tobacco smoking and the development of endothelial dysfunction. In contrast to low laminar flow, high laminar flow mediates protective effects on tobacco smoke-induced endothelial inflammation and wound healing.

Cigarette smoke extract abrogates atheroprotective effects of high laminar flow on endothelial function

Abstract

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Professor Henning Morawietz

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Poster session 3 - Endothelium

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Frontiers in CardioVascular Biology 2016