title: Low density lipoprotein induces upregulation of vasoconstrictive endothelin type B receptor expression.
abstract: Vasoconstrictive endothelin type B (ET(B)) receptors promote vasospasm and ischemic cerebro- and cardiovascular diseases. The present study was designed to examine if low density lipoprotein (LDL) induces upregulation of vasoconstrictive ET(B) receptor expression and if extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signal pathways are involved in this process. Rat mesenteric artery segments were organ cultured in the presence and absence of LDL with or without inhibitors for MAPK kinase 1 and 2 (MEK1/2), p38 and transcription. The upregulation of vasoconstrictive ET(B) receptor expression was studied using a sensitive myograph, real-time PCR and Western blot. LDL (11, 22 and 44 mg protein/L) concentration-dependently induced upregulation of vasoconstrictive ETB receptor expression with increase in the receptor-mediated vasoconstriction, elevated levels of the ET(B) receptor mRNA and protein expressions, and activation of ERK1/2 and p38 MAPK. Blockage of ERK1/2 and p38 MAPK signal pathways using MEK1/2 inhibitors (PD98059 and U0126) or p38 inhibitors (SB203580 and SB239063) significantly abolished the LDL-induced upregulation of vasoconstrictive ET(B) receptor expression. Actinomycin D (general transcriptional inhibitor) almost completely inhibited the LDL effects. In conclusion, LDL induces upregulation of vasoconstrictive ET(B) receptor expression through activation of ERK1/2 and p38 MAPK signal pathway-dependent transcriptional mechanisms.
authors: 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. Electronic address: cangbaoxu@yahoo.com.
authors: Cang-Bao
authors: CB
authors: Xu
authors: Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden.
authors: Jian-Pu
authors: JP
authors: Zheng
authors: Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden.
authors: Wei
authors: W
authors: Zhang
authors: Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, Xi'an, China.
authors: Enqi
authors: E
authors: Liu
authors: Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden.
authors: Lars
authors: L
authors: Edvinsson
authors: 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: Yaping
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; C099252:oxidized low density lipoprotein; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Actinomycin D (PubChem CID: 2019); Endothelin receptor; Ischemia; LDL; MAPK; PD98059 (PubChem CID: 4713); SB203580 (PubChem CID: 176155); SB239063 (PubChem CID: 5166); Sarafotoxin 6c (PubChem CID: 16132429); U0126 (PubChem CID: 3006531); Vasoconstriction