Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1

Aims 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 th...

Full description

Saved in:
Bibliographic Details
Published in:Cardiovascular research 2009-01, Vol.81 (1), p.226-234
Main Authors: Satoh, Kimio, Fukumoto, Yoshihiro, Nakano, Makoto, Sugimura, Koichiro, Nawata, Jun, Demachi, Jun, Karibe, Akihiko, Kagaya, Yutaka, Ishii, Naoto, Sugamura, Kazuo, Shimokawa, Hiroaki
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Biological and medical sciences
Bone Marrow Cells - cytology
Bone Marrow Cells - metabolism
Cardiology. Vascular system
CD18 Antigens - metabolism
Cell Differentiation - physiology
Cells, Cultured
Chemokine CXCL12 - drug effects
Chemokine CXCL12 - genetics
Chemokine CXCL12 - metabolism
Disease Models, Animal
Down-Regulation - drug effects
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
Hypertension, Pulmonary - etiology
Hypertension, Pulmonary - metabolism
Hypertension, Pulmonary - prevention & control
Hypoxia
Hypoxia - complications
Intercellular Adhesion Molecule-1 - metabolism
Medical sciences
Mice
Mice, Inbred BALB C
Muscle, Smooth, Vascular - cytology
Muscle, Smooth, Vascular - metabolism
Myofibroblast
Pneumology
Pravastatin - pharmacology
Progenitors
Proto-Oncogene Proteins c-kit - metabolism
Pulmonary hypertension
Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases
Receptors, CXCR4 - metabolism
Statin
Stem Cells - cytology
Stem Cells - metabolism
Vascular Endothelial Growth Factor Receptor-2 - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Aims 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. Methods and results Chronic hypoxia (10% O2 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 α-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 (β2-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.
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvn244