title: Secondhand smoke exposure induces Raf/ERK/MAPK-mediated upregulation of cerebrovascular endothelin ETA receptors.
abstract: BACKGROUND
  Cigarette smoking enhances the risk of stroke. However, the underlying molecular mechanisms are largely unknown. The present study established an in vivo rat secondhand cigarette smoking (SHS) model and examined the hypothesis that SHS upregulates endothelin receptors with increased cerebrovascular contraction via the Raf/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) pathway.
  
  
  RESULTS
  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 (P < 0.05) mediated by endothelin type A (ETA) receptors. The expressions of mRNA and protein for ETA receptors in the cerebral arteries from SHS rats were higher (P < 0.05) than that in control. SHS did not affect endothelin type B (ETB) receptor-mediated contractions, mRNA or protein levels. The results suggest that SHS upregulates ETA, but not ETB receptors in vivo. 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 (P < 0.05). Raf-1 inhibitor, GW5074 suppressed the enhanced ETA receptor-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.
  
  
  CONCLUSIONS
  SHS upregulates cerebrovascular ETA receptors via the Raf/ERK/MAPK pathway, which provides novel understanding of mechanisms involved in SHS-associated stroke.
authors: Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Sweden.
authors: Lei
authors: L
authors: Cao
authors: Cang-Bao
authors: CB
authors: Xu
authors: Yaping
authors: Y
authors: Zhang
authors: Yong-Xiao
authors: YX
authors: Cao
authors: Lars
authors: L
authors: Edvinsson
mesh_terms: D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000096:biosynthesis* / Q000235:genetics; D020521:Stroke / Q000201:enzymology* / Q000209:etiology* / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D015854:Up-Regulation / Q000502:physiology*; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D044022:Receptor, Endothelin A; D014028:Tobacco Smoke Pollution; D048490:raf Kinases