Cigarette Smoke Extracts Promote Vascular Smooth Muscle Cell Proliferation and Enhances Contractile Responses in the Vasculature and Airway

Abstract

Cigarette smoke exposure is a strong risk factor for cardiovascular and respiratory diseases. However, the knowledge about how cigarette smoke induces damage to vasculature and airway is limited. The present study was designed to examine the effects of cigarette smoke particles extracted by heptane (heptane-soluble smoke particles, HSP), by water (watersoluble smoke particles, WSP) and by DMSO (DMSO-soluble smoke particles, DSP), which represent lipophilic, hydrophilic and ambiphoteric constituents from the cigarette smoke, respectively. Human aortic smooth muscle cell (HASMC) proliferation was assessed in cell culture. Rat resistance artery and airway contractile responses to serotonin, U46619, phenylephrine, noradrenaline, acetylcholine, des-Arg 9 -bradykinin, bradykinin, sarafotoxin 6c and endothelin-1 were monitored by a sensitive myograph system. Immunocytochemistry and cell-based phosphoELISA assay were used to demonstrate activation of extracellular signal-regulated kinases 1 ⁄ 2 (ERK1 ⁄ 2). For the first time, our results demonstrate that although all the three extracts promote HASMC proliferation, the HSP and DSP effects occur earlier. HSP and DSP, but not WSP, increase the contractile responses to sarafotoxin 6c, U46619 or bradykinin in rat mesenteric artery and ⁄ or in bronchi. ERK1 ⁄ 2 is activated by HSP and DSP in HASMCs and inhibition of ERK1 ⁄ 2 abrogated the smoke extracts-induced HASMC proliferation, while blockage of nicotinic receptors had no effects, suggesting that the toxic effects of the smoke extracts occur via activation of intracellular ERK1 ⁄ 2 signalling, but not nicotinic receptors.Exposure to cigarette smoke is strongly associated with cardiovascular diseases like atherosclerosis, coronary heart disease, stroke, myocardial infarction, aortic aneurysm and peripheral vascular disease [1,2]. In airways, cigarette smoke, via direct smoking or second-hand inhalation, exacerbates chronic obstructive pulmonary disease (COPD), chronic bronchitis and asthma and also causes lung cancer. An estimated 1.6 million cardiovascular deaths worldwide are attributable to smoking [3] and about 73% of the COPD mortality is related to cigarette smoke exposure [4]. However, our knowledge about how cigarette smoke induces cardiovascular and airway diseases is very limited.Cigarette smoke contains over 4000 different compounds. Among them, 158 chemical constituents of smoke are identified to be toxic hazards. Of the 17 non-cancer compounds, based on a non-cancer risk index, 15 individual chemical constituents contribute to the respiratory irritation and the cardiovascular dysfunction [5]. Previously, we have revealed that DMSO-soluble smoke particles (DSP), but not nicotine or water-soluble cigarette smoke particles (WSP), induce dysfunctions of vascular smooth muscle cells [6] suggesting that it is the lipid-soluble particles from cigarette smoke that are responsible for the toxic effects. Furthermore, DSP exerts a direct toxic effect on vascular endothelial cells and reduces endothelium-depende...

Alteration of Airway Reactivity and Reduction of Ryanodine Receptor Expression by Cigarette Smoke in Mice

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MAPK/NF-κB-dependent upregulation of kinin receptors mediates airway hyperreactivity: A new perspective for the treatment

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Differences and Interactions between Risk Factors for Coronary Spasm and Atherosclerosis -Smoking, Aging, Inflammation, and Blood Pressure-

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