title: Lipid-soluble Cigarette Smoke Particles Induced Vascular Endothelin Type A Receptor Up-Regulation through Activation of ERK1/2 Signal Pathways.
abstract: Abnormal contraction of vessels termed 'vasospasm' is associated with various cardiovascular diseases. Smoking is a well-known risk factor that increases vasospasm. However, the molecular mechanisms by which smoking leads to vasospasm and cardiovascular disease are not fully understood. This study was designed to examine whether DMSO-extracted cigarette smoke particles (DSP) could induce up-regulation of vascular endothelin type A (ETA) receptors, and whether ETAreceptor is up-regulated through activation of extracellular regulated protein kinases 1 and 2 (ERK1/2) signal pathways. Mesenteric arterial segments from rats were cultured in the presence of DSP, water-extracted cigarette smoke particles (WSP) or equivalent concentration of nicotine for up to 24 hr. The results showed that DSP, but not WSP or nicotine, induced ETAreceptor up-regulation with increased ETAreceptor-mediated contraction (myograph, p < 0.001). Simultaneously, the expression of ETAreceptor mRNA (real-time PCR, p < 0.001) and protein (immunohistochemistry) were enhanced in the smooth muscle cells, suggesting that the lipid-soluble substances contained in cigarette smoke were responsible for the effects of DSP. Actinomycin D (a general transcriptional inhibitor) decreased ETAreceptor mRNA expression and attenuated receptor-mediated contraction (p < 0.001), while DSP accelerated ETAreceptor mRNA degradation (p < 0.01) and promoted the translation of ETAreceptor mRNA into protein. Furthermore, the up-regulation of ETAreceptors was significantly attenuated by inhibition of ERK1/2 signal pathways (p < 0.001). In conclusion, DSP most likely activate ERK1/2 signal pathway-mediated transcriptional and post-transcriptional (translational) mechanisms that lead to vascular ETAreceptor up-regulation, which might contribute to vasospasm and the development of smoking-associated cardiovascular diseases.
authors.affiliation: Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden.|Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
authors.affiliation: Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China.|Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden.
authors.forename: Cang-Bao
authors.initials: CB
authors.lastname: Xu
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008055:Lipids / Q000737:chemistry*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects* / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D052638:Particulate Matter / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D044022:Receptor, Endothelin A / Q000235:genetics*; D015398:Signal Transduction; D012995:Solubility; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D008055:Lipids; D052638:Particulate Matter; D044022:Receptor, Endothelin A; D014028:Tobacco Smoke Pollution