Lipid-soluble smoke particles upregulate vascular smooth muscle ETB receptors via activation of mitogen-activating protein kinases and NF-kappaB pathways

Cang-Bao Xu, Jian-Pu Zheng, Wei Zhang, Yaping Zhang, Lars Edvinsson
Toxicological Sciences: An Official Journal of the Society of Toxicology 2008, 106 (2): 546-55
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 (ET(B)) receptors in arterial smooth muscle cells. The increased ET(B) receptors in arterial smooth muscle cells was documented as enhanced contractility (sensitive myograph technique), elevated levels of ET(B) 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-kappaB) phosphorylation within 3 h. Blocking ERK1/2, p38, or NF-kappaB activation by their specific inhibitors significantly attenuated the DSP-induced upregulation of ET(B) receptor-mediated contraction and both ET(B) receptor mRNA and protein expression. In addition, dexamethasone abolished the DSP-induced upregulation of ET(B) receptor-mediated contraction. In conclusion, upregulation of ET(B) 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-kappaB pathways.

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