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ToxSci Advance Access originally published online on August 20, 2008
Toxicological Sciences 2008 106(2):546-555; doi:10.1093/toxsci/kfn173
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Lipid-Soluble Smoke Particles Upregulate Vascular Smooth Muscle ETB Receptors via Activation of Mitogen-Activating Protein Kinases and NF-kappaB Pathways

Cang-Bao Xu*,{dagger},1, Jian-Pu Zheng*, Wei Zhang{dagger}, Yaping Zhang{dagger} and Lars Edvinsson*,{dagger}

* Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, 221 84 Lund, Sweden {dagger} Department of Clinical and Experimental Research, Glostrup Hospital, Copenhagen University, 2600 Glostrup, Copenhagen, Denmark

1 To whom correspondence should be addressed at the Division of Experimental Vascular Research, BMC A13, WNC, Institute of Clinical Science in Lund, Lund University, 221 84 Lund, Sweden. Fax: +46-46-2220616. E-mail: Cang-Bao.Xu{at}med.lu.se.

Received May 9, 2008; accepted August 12, 2008


  Abstract

Cigarette smoke is a strong risk factor for cardiovascular disease. However, the underlying molecular mechanisms that lead to cigarette smoke–associated cardiovascular disease remain elusive. With functional and molecular methods, we demonstrate for the first time that lipid-soluble cigarette smoke particles (dimethylsulfoxide-soluble cigarette smoke particles; DSP) increased the expression of endothelin type B (ETB) receptors in arterial smooth muscle cells. The increased ETB receptors in arterial smooth muscle cells was documented as enhanced contractility (sensitive myograph technique), elevated levels of ETB receptor mRNA (quantitative real-time PCR), and protein expressions (immunohistochemistry and Western blotting). Intracellular signaling was studied with Western blotting and phosphoELISA; this revealed that DSP induced extracellular-regulated protein kinases 1 and 2 (ERK1/2), p38, and nuclear factor–kappaB (NF-{kappa}B) phosphorylation within 3 h. Blocking ERK1/2, p38, or NF-{kappa}B activation by their specific inhibitors significantly attenuated the DSP-induced upregulation of ETB receptor–mediated contraction and both ETB receptor mRNA and protein expression. In addition, dexamethasone abolished the DSP-induced upregulation of ETB receptor–mediated contraction. In conclusion, upregulation of ETB receptors by DSP in arterial smooth muscle cells involves activation of mitogen-activating protein kinases (ERK1/2 and p38) and the downstream transcriptional factor NF-{kappa}B pathways.

Key Words: smoking; ETB receptor; MAPK; VSMC; vascular disease.


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