title: Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1.
abstract: OBJECTIVE
  Mobilization of stem cells/progenitors is regulated by the interaction between stromal cell-derived factor-1 (SDF-1) and its ligand, CXC chemokine receptor 4 (CXCR4). Statins have been suggested to ameliorate pulmonary arterial hypertension (PAH); however, the mechanisms involved, especially their effects on progenitors, are largely unknown. Therefore, we examined whether pravastatin ameliorates hypoxia-induced PAH in mice, and if so, which type of progenitors and what mechanism(s) are involved.
  
  
  RESULTS
  Chronic hypoxia (10% O(2) for 5 weeks) increased the plasma levels of SDF-1 and mobilization of CXCR4(+)/vascular endothelial growth factor receptor (VEGFR)2(+)/c-kit(+) cells from bone marrow (BM) to pulmonary artery adventitia in Balb/c mice in vivo, both of which were significantly suppressed by simultaneous oral treatment with pravastatin (2 mg/kg/day). Furthermore, in vitro experiments demonstrated that hypoxia enhances differentiation of VEGFR2(+)/c-kit(+) cells into alpha-smooth muscle actin(+) cells. Importantly, pravastatin ameliorated hypoxia-induced PAH associated with a decrease in the number of BM-derived progenitors accumulating in the pulmonary artery adventitia. The expression of intercellular adhesion molecule-1 (ICAM-1) and its ligand, CD18 (beta2-integrin), were enhanced by hypoxia and were again suppressed by pravastatin.
  
  
  CONCLUSIONS
  These results suggest that pravastatin ameliorates hypoxia-induced PAH through suppression of SDF-1/CXCR4 and ICAM-1/CD18 pathways with a resultant reduction in the mobilization and homing of BM-derived progenitor cells.
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakano
authors.forename: Koichiro
authors.initials: K
authors.lastname: Sugimura
authors.forename: Jun
authors.initials: J
authors.lastname: Nawata
authors.forename: Jun
authors.initials: J
authors.lastname: Demachi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Karibe
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kagaya
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000199:Actins; D018821:CD18 Antigens; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019718:Receptors, CXCR4; D018799:Intercellular Adhesion Molecule-1; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2; D017035:Pravastatin