Abstract
Cigarette smoking is one of the most important and preventable risk factors for atherosclerosis. However, because of the complex composition of cigarette smoke, the detailed pathophysiological mechanisms are not fully understood. Based on controversial reports on the pro-atherogenic activity of cigarette smoke condensate, also called tar fraction (CSC), we decided to analyse the effects of CSC on the viability of endothelial cells in vitro. The results of this study show that low concentrations of the hydrophobic tar fraction induces DNA damage resulting in a P53-dependent and BCL-XL-inhibitable death cascade. Western blot analyses showed that this cascade is caspase-independent and immunofluorescence analysis have shown that the apoptotic death signalling is mediated by the release of apoptosis-inducing factor. Higher CSC concentrations also induce apoptotic-like signalling but the signalling cascade is then redirected to necrosis. Despite the fact that CSC induces a profound increase in cellular reactive oxygen species production, antioxidants exhibit only a minimal cell death protective effect. Our data indicates that not only hydrophilic constituents of cigarette smoke extract, but also CSC is harmful to endothelial cells. The mode and the outcome of CSC-induced cell death signalling are highly concentration dependent: lower concentrations induce caspase-independent apoptosis-like cell death, whereas incubation with higher concentrations interrupts apoptotic signalling and induces necrosis.
Highlights
Cigarette smoke is subdivided into two phases: the hydrophobic tar or particulate fraction, and the hydrophilic or gas phase.[5]
As the clear definition of cell death endpoints is crucial for the pathophysiology of atherosclerosis this project aims at investigating the effects of CSC on endothelial viability in vitro, focussing on the execution of CSC-induced cell death
The most relevant difference of necrotic cell death compared to apoptosis is plasma membrane leakage and the resulting induction of inflammation in the affected tissue caused by the release of intracellular components.[9,11]
Summary
Cigarette smoke is subdivided into two phases: the hydrophobic tar (cigarette smoke condensate, CSC) or particulate fraction, and the hydrophilic or gas phase (cigarette smoke extract, CSE).[5]. It is generally accepted that atherosclerosis is a multifactorial disease and many atherogenic processes lead to similar patho-biological effects. Of these effects, endothelial cell death (and endothelial dysfunction) takes a central role in atherogenesis.[7,8] At the same time, the loss of endothelial cells has direct functional effects, but it is crucial, which form of cell death is induced. Abbrevations: CSC, cigarette smoke condensate; CSE, cigarette smoke extract; AIF, apoptosis inducing factor; LC3, microtubule associated protein light chain 3; LDH, lactate dehydrogenase; ATP, adenosine triphosphate; ROS, reactive oxygen species; 3-MA, 3-methyladenine; NAC, N-acetylcysteine; DHR, dihydrorhodamine. The most relevant difference of necrotic cell death compared to apoptosis is plasma membrane leakage and the resulting induction of inflammation in the affected tissue caused by the release of intracellular components.[9,11]
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