Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1
Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1
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DOI：
10.1093/cvr/cvn244
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发表时间：
2009-01-01
影响因子：
10.8
通讯作者：
Shimokawa, Hiroaki
中科院分区：
文献类型：
--
作者：
Satoh, Kimio;Fukumoto, Yoshihiro;Shimokawa, Hiroaki
干细胞/祖细胞的动员受基质细胞衍生因子-1（SDF-1）及其配体CXC趋化因子受体4（CXCR 4）之间的相互作用调节。他汀类药物已被认为可以改善肺动脉高压（PAH）;然而，所涉及的机制，特别是其对祖细胞的影响，在很大程度上是未知的。因此，我们研究了普伐他汀是否能改善小鼠缺氧诱导的PAH，如果是，哪种类型的祖细胞和什么样的机制（S）参与。慢性缺氧（10%O-2，5周）增加了Balb/c小鼠血浆SDF-1水平和CXCR 4（+）/血管内皮生长因子受体（VEGFR）2（+）/c-kit（+）细胞从骨髓（BM）向肺动脉外膜的动员。c小鼠体内，这两种情况均被普伐他汀（2 mg/kg/天）同时口服治疗显著抑制。此外，体外实验表明，缺氧促进VEGFR 2（+）/c-kit（+）细胞向α-平滑肌肌动蛋白（+）细胞的分化。重要的是，普伐他汀改善了缺氧诱导的PAH，与肺动脉外膜中积累的BM衍生祖细胞数量减少相关。缺氧可使肺动脉高压大鼠肺组织细胞间粘附分子-1（ICAM-1）及其配体CD 18（β 2-integrin）的表达增强，而普伐他汀可抑制ICAM-1及其配体CD 18的表达，提示普伐他汀可通过抑制SDF-1/CXCR 4和ICAM-1/CD 18通路，减少骨髓源性祖细胞的动员和归巢，从而减轻缺氧诱导的肺动脉高压。
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.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 (beta 2-integrin), were enhanced by hypoxia and were again suppressed by pravastatin.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.