Journal Article

Lipid-Soluble Smoke Particles Upregulate Vascular Smooth Muscle ET<sub>B</sub> Receptors via Activation of Mitogen-Activating Protein Kinases and NF-kappaB Pathways

Cang-Bao Xu, Jian-Pu Zheng, Wei Zhang, Yaping Zhang and Lars Edvinsson

in Toxicological Sciences

Volume 106, issue 2, pages 546-555
Published in print December 2008 | ISSN: 1096-6080
Published online August 2008 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfn173
Lipid-Soluble Smoke Particles Upregulate Vascular Smooth Muscle ETB Receptors via Activation of Mitogen-Activating Protein Kinases and NF-kappaB Pathways

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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-κB) phosphorylation within 3 h. Blocking ERK1/2, p38, or NF-κB 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-κB pathways.

Keywords: smoking; ETB receptor; MAPK; VSMC; vascular disease

Journal Article.  4861 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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