title: The effects of MEK1/2 inhibition on cigarette smoke exposure-induced ET receptor upregulation in rat cerebral arteries.
abstract: Cigarette smoking, a major stroke risk factor, upregulates endothelin receptors in cerebral arteries. The present study examined the effects of MEK1/2 pathway inhibition on cigarette smoke exposure-induced ET receptor upregulation. Rats were exposed to the secondhand smoke (SHS) for 8weeks followed by intraperitoneal injection of MEK1/2 inhibitor, U0126 for another 4weeks. The urine cotinine levels were assessed with high-performance liquid chromatography. Contractile responses of isolated cerebral arteries were recorded by a sensitive wire myograph. The mRNA and protein expression levels of receptor and MEK/ERK1/2 pathway molecules were examined by real-time PCR and Western blotting, respectively. Cerebral artery receptor localization was determined with immunohistochemistry. The results showed the urine cotinine levels from SHS exposure group were significantly higher than those from the fresh group. In addition, the MEK1/2 inhibitor, U0126 significantly reduced SHS exposure-increased ETA receptor mRNA and protein levels as well as contractile responses mediated by ETA receptors. The immunoreactivity of increased ETA receptor expression was primarily cytoplasmic in smooth muscle cells. In contrast, ETB receptor was noted in endothelial cells. However, the SHS-induced decrease in endothelium-dependent relaxation was unchanged after U0126 treatment. Furthermore, SHS increased the phosphorylation of MEK1/2 and ERK1/2 protein in cerebral arteries. By using U0126 could inhibit the phosphorylated ERK1/2 protein but not MEK1/2. Taken together, our data show that treatment with MEK1/2 pathway inhibitor offsets SHS exposure-induced ETA receptor upregulation in rat cerebral arteries.
authors.affiliation: Division of Experimental Vascular Research, Institute of Clinical Sciences in Lund, Lund University, Sweden; Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Ping
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Yong-Xiao
authors.initials: YX
authors.lastname: Cao
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. Electronic address: 13572512207@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Division of Experimental Vascular Research, Institute of Clinical Sciences in Lund, Lund University, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Warfvinge
authors.affiliation: Division of Experimental Vascular Research, Institute of Clinical Sciences in Lund, Lund University, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects*; D003367:Cotinine / Q000652:urine; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D044022:Receptor, Endothelin A / Q000096:biosynthesis* / Q000187:drug effects; D044023:Receptor, Endothelin B / Q000096:biosynthesis* / Q000187:drug effects; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D002070:Butadienes; D009570:Nitriles; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014028:Tobacco Smoke Pollution; C113580:U 0126; D003367:Cotinine
keywords: Cerebral artery; Cigarette smoke; Endothelin receptor; MEK1/2; Rat; Receptor upregulation