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

Kimio Satoh, Yoshihiro Fukumoto, Makoto Nakano, Koichiro Sugimura, Jun Nawata, Jun Demachi, Akihiko Karibe, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)226-234
Number of pages9
JournalCardiovascular Research
Volume81
Issue number1
DOIs
Publication statusPublished - 2009 Jan

Keywords

  • Hypoxia
  • Myofibroblast
  • Progenitors
  • Pulmonary hypertension
  • Statin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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