Abstract
BackgroundCigarette 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.ResultsRats 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.ConclusionsSHS upregulates cerebrovascular ETA receptors via the Raf/ERK/MAPK pathway, which provides novel understanding of mechanisms involved in SHS-associated stroke.
Highlights
Cigarette smoking enhances the risk of stroke
General There was no significant difference in cerebral artery contractile responses to K+, sarafotoxin 6 c (S6c) and ET-1 after 2 or 4 weeks in secondhand cigarette smoking (SHS) exposed rats as compared to rats exposed to fresh air for a similar time period (Table 1)
The vasoconstriction induced by a combined endothelin type A (ETA) and endothelin type B (ETB) receptor agonist ET-1 was studied after desensitizing the ETB receptors with S6c prior to adding ET-1, leaving only ETA receptors to respond
Summary
Cigarette smoking enhances the risk of stroke. 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. To the best of our knowledge, it has not been studied if SHS in vivo is associated with elevated expression of ET receptors. If both the formation of ET-1 and the number of contractile ET receptors are increased in individuals after exposure to SHS, it may bring about larger damage in SAH or cerebral infarct, compared to the non-smokers. We hypothesize that SHS exposure in vivo upregulates ET receptors in cerebral arteries, which may in turn contribute to larger brain damage in stroke among smoke exposed subjects
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