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

• Published in: Cardiovascular research Vol. 81; no. 1; pp. 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: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2009
• 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; Hypoxia; Statin; Progenitors; Myofibroblast; Pulmonary hypertension; Oxygen; Respiratory disease; Cardiovascular disease; Statin derivative; Phlebology; Stromal cell derived factor 1; Regulation(control); Association; Circulatory system; Cardiology; CXC chemokine
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvn244

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.