title: Regulation of mitogen-activated protein kinase cascades by low density lipoprotein and lysophosphatidic acid.
abstract: Aim of the present study was to elucidate the regulation of the mitogen activated protein (MAP) kinase cascades as well as the cross-talk between the various MAP kinase isoforms (ERK1/2, SAPK and p38) after stimulation of vascular smooth muscle cells (VSMC) with low density lipoprotein (LDL), 100 microg/ml or lysophosphatidic acid (LPA), 5 microg/ml. Furthermore, the role of the intracellular free Ca(2+) concentration ([Ca(2+)](i)) on the activation of the MAP kinase isoforms as well as on the protein expression of MAP kinase phosphatase (MKP)-1 was investigated. The methods used were Western blot analysis, immunoprecipitation and LDL isolation. Involvement of G(i)-proteins on LDL- and LPA-induced activation of the MAP kinase isoforms was examined by treatment of VSMC with pertussis toxin (PTX),100 ng/ml. LDL as well as LPA induced an activation of SAPK and p38 MAP kinase in a PTX-sensitive manner. The ERK1/2, SAPK and p38 MAP kinase activation was a Ca(2+)-dependent process, most likely regulated through modulation of MKP-1 protein expression. Inhibition of ERK1/2 by PD 98059 completely abolished LDL- and LPA-induced activation of SAPK, whereas the activation of p38 MAP kinase was not affected. We conclude, that [Ca(2+)](i) regulates the PTX-sensitive LDL- and LPA-induced stimulation of the MAP kinase cascades, probably via inhibition of the MKP-1 protein expression.
authors.affiliation: Medizinische Universitäts-Poliklinik Bonn.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Gouni-Berthold
authors.forename: Stefan
authors.initials: S
authors.lastname: Seewald
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.forename: Agapios
authors.initials: A
authors.lastname: Sachinidis
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY
chemical_list: D018797:Cell Cycle Proteins; D005419:Flavonoids; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D037342:Pertussis Toxin; D048049:Extracellular Signal-Regulated MAP Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C032881:lysophosphatidic acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one