Secondhand smoke exposure induces Raf/ERK/MAPK-mediated upregulation of cerebrovascular endothelin ET_Areceptors

• Main Authors: Cao Yong-Xiao, Zhang Yaping, Xu Cang-Bao, Cao Lei, Edvinsson Lars
• Format: Article
• Language: English
• Published: BMC 2011-11-01
• Series: BMC Neuroscience
• Online Access: http://www.biomedcentral.com/1471-2202/12/109

<p>Abstract</p> <p>Background</p> <p>Cigarette smoking enhances the risk of stroke. However, the underlying molecular mechanisms are largely unknown. The present study established an <it>in vivo </it>rat secondhand cigarette smoking (SHS) model and examined the hypothesis that SHS upregulates endothelin receptors with increased cerebrovascular contraction <it>via </it>the Raf/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) pathway.</p> <p>Results</p> <p>Rats were exposed to SHS for up to 8 weeks. The cerebral artery vasoconstriction was recorded by a sensitive myograph. The mRNA and protein expressions for endothelin receptors in cerebral arteries were studied by real-time PCR and Western blot. Compared to fresh air exposed rats, cerebral arteries from SHS rats exhibited stronger contractile responses (<it>P </it>< 0.05) mediated by endothelin type A (ET_A) receptors. The expressions of mRNA and protein for ET_Areceptors in the cerebral arteries from SHS rats were higher (<it>P </it>< 0.05) than that in control. SHS did not affect endothelin type B (ET_B) receptor-mediated contractions, mRNA or protein levels. The results suggest that SHS upregulates ET_A, but not ET_Breceptors <it>in vivo</it>. After SHS exposure, the mRNA levels of Raf-1 and ERK1/2, the protein expression of phosphorylated (p)-Raf-1 and p-ERK1/2 were increased (<it>P </it>< 0.05). Raf-1 inhibitor, GW5074 suppressed the enhanced ET_Areceptor-mediated contraction, mRNA and protein levels induced by SHS. In addition, GW5074 inhibited the SHS-caused increased mRNA and phosphorylated protein levels of Raf-1 and ERK1/2, suggesting that SHS induces activation of the Raf/ERK/MAPK pathway.</p> <p>Conclusions</p> <p>SHS upregulates cerebrovascular ET_Areceptors <it>via </it>the Raf/ERK/MAPK pathway, which provides novel understanding of mechanisms involved in SHS-associated stroke.</p>