title: Involvement of apoptosis signal-regulating kinase-1 on angiotensin II-induced monocyte chemoattractant protein-1 expression.
abstract: OBJECTIVE
  Monocyte chemoattractant protein 1 (MCP-1) could contribute to enhanced leukocyte recruitment and activation resulting in chronic tissue damage. However, little is known about the molecular mechanisms of cardiac MCP-1 expression. To elucidate these molecular mechanisms, angiotensin II-induced expression of MCP-1 was examined in cultured rat neonatal ventricular cardiomyocytes and fibroblasts by adenovirus gene transfer.
  
  
  RESULTS
  MCP-1 mRNA increased 3.6-fold in cardiac fibroblasts at 3 hours after 100 nmol/L angiotensin-II stimulation (P<0.01), whereas MCP-1 mRNA in cardiomyocytes was unchanged. Angiotensin II significantly enhanced JNK, p38MAPK, and nuclear factor-kappaB (NF-kappaB) activities of cardiac fibroblasts. Wild-type ASK-1 increased MCP-1 expression of cardiac fibroblasts, whereas dominant negative mutant of ASK-1 (DN-ASK), dominant negative mutant of p38MAPK (DN-p38MAPK), and pyrrolidine dithiocarbamate significantly inhibited such expression. The increased MCP-1 mRNA expression in wild-type ASK-1 transfected fibroblasts was inhibited by cotransfection with adenovirus expressing DN-p38MAPK. On the contrary, the decreased MCP-1 mRNA expression in DN-ASK transfected cells was increased by cotransfection with adenovirus expressing constitutively active MKK6.
  
  
  CONCLUSIONS
  Angiotensin II induced MCP-1 gene expression in cardiac fibroblasts. The angiotensin II-induced activation of ASK-1 followed by p38MAPK and NF-kappaB signaling in cardiac fibroblasts is partially involved in myocardial MCP-1 expression.
authors.affiliation: Department of Internal Medicine and Cardiology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. omura@med.osaka-cu.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Omura
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshiyama
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim
authors.forename: Ryo
authors.initials: R
authors.lastname: Matsumoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yasukatsu
authors.initials: Y
authors.lastname: Izumi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Sudo
authors.forename: Kaname
authors.initials: K
authors.lastname: Akioka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwao
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshikawa
mesh_terms: D000256:Adenoviridae; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D005419:Flavonoids / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology / Q000201:enzymology; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D032342:Muscle Cells / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D009154:Mutation / Q000235:genetics / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016328:NF-kappa B; D012333:RNA, Messenger; D000804:Angiotensin II; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one