Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 8, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn244
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Statin Ameliorates Hypoxia-Induced Pulmonary Hypertension Associated with Down-regulated Stromal Cell-Derived Factor-1
1 Departments of Cardiovascular Medicine Tohoku University Graduate School of Medicine, Sendai, Japan
2 Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
3 Technology Agency, CREST, Tokyo, Japan
Address for Correspondence: Yoshihiro Fukumoto, MD, PhD Department of Cardiovascular Medicine Tohoku University Graduate School of Medicine 1-1 Seiryo-machi, Aoba-ku Sendai 980-8574, JAPAN (Tel) +81-22-717-7153, (Fax) +81-22-717-7156 (EM) fukumoto{at}cardio.med.tohoku.ac.jp
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 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 
-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. (208 words)
KEYWORDS statin; pulmonary hypertension; hypoxia; myofibroblast; progenitors
Time for primary review: 29 days
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