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: Lei Cao, Na-Na Ping, Yong-Xiao Cao, Wei Li, Yan Cai, Karin Warfvinge, Lars Edvinsson
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 304 Pg. 70-8 (08 01 2016) ISSN: 1096-0333 [Electronic] United States
• PMID: 27212444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Butadienes
• Nitriles
• RNA, Messenger
• Receptor, Endothelin A
• Receptor, Endothelin B
• Tobacco Smoke Pollution
• U 0126
• Cotinine

Topics

• Animals
• Butadienes (pharmacology)
• Cerebral Arteries (drug effects)
• Cotinine (urine)
• MAP Kinase Signaling System (drug effects)
• Male
• Nitriles (pharmacology)
• RNA, Messenger (biosynthesis)
• Rats
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Receptor, Endothelin A (biosynthesis, drug effects)
• Receptor, Endothelin B (biosynthesis, drug effects)
• Tobacco Smoke Pollution (adverse effects)
• Up-Regulation
• Vasoconstriction (drug effects)