title: Cyclosporin A upregulates ETB receptor in vascular smooth muscle via activation of mitogen-activating protein kinases and NF-κB pathways.
abstract: Hypertension is one of the most frequent complications of solid organ transplantation, and cyclosporin A (CsA) plays a predominant role in the pathophysiology of post-transplant hypertension. However, the exact molecular mechanisms of CsA-induced hypertension remain obscure. We previously showed that CsA increased the mRNA expression and contractile function of endothelin B (ETB) receptor in vascular smooth muscle cells. The present study was designed to investigate the underlying mechanisms of CsA-induced upregulation of ETB receptor in vasculature. Rat mesenteric arteries were incubated with CsA in an organ culture system, and results showed that CsA enhanced ETB receptor mRNA in the time- and dose-dependent manner, and increased protein expression levels of ETB receptor after treatment with CsA 10(-5)M for 6h. Furthermore, CsA induced phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2), p38, and translocation of nuclear factor-kappaB (NF-κB) p65 in vasculature. Blocking ERK1/2, p38, or NF-κB activation with their specific inhibitors markedly attenuated CsA-induced upregulation of ETB receptor mRNA expression and protein levels, and ETB receptor-mediated contraction. In summary, this study showed that mitogen-activating protein kinases (ERK1/2 and p38) and the downstream transcriptional factor NF-κB pathways were involved in CsA-induced upregulation of ETB receptor in arterial smooth muscle cells.
authors.affiliation: Experimental Research Center, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Cardiology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Jian-Pu
authors.initials: JP
authors.lastname: Zheng
authors.affiliation: Department of Cardiology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Zhuoan
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Experimental Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Jiaye
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Experimental Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: keyantcm@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Department of Cardiology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: lzjgroup@126.com.
authors.forename: Zongjun
authors.initials: Z
authors.lastname: Liu
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology; D004789:Enzyme Activation; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000201:enzymology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009924:Organ Culture Techniques; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D044023:Receptor, Endothelin B / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D065131:Endothelin B Receptor Antagonists; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D016572:Cyclosporine; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Cyclosporin A; ET(B) receptor; MAPK; NF-κB; VSMC