过氧化物酶体增殖物激活受体 α 通过 HIF-1α/SDF-1 通路调节内皮祖细胞的动员和归巢。
PPARα regulates mobilization and homing of endothelial progenitor cells through the HIF-1α/SDF-1 pathway.
机构信息
Department of Ophthalmology, Shanghai First People's Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
出版信息
Invest Ophthalmol Vis Sci. 2014 May 20;55(6):3820-32. doi: 10.1167/iovs.13-13396.
PURPOSE
The mechanism for the antiangiogenic activity of peroxisome proliferator-activated receptor alpha (PPARα) remains incompletely understood. Endothelial progenitor cells (EPC) are known to participate in neovascularization (NV). The purpose of this study was to investigate whether PPARα regulates EPC during retinal NV.
METHODS
Retinal NV was induced by oxygen-induced retinopathy (OIR). Mice with OIR were injected intraperitoneally with the PPARα agonist fenofibric acid (FA) or with adenovirus expressing PPARα (Ad-PPARα). Flow cytometry was used to quantify circulating and retinal EPC. Serum stromal cell-derived factor 1 (SDF-1) levels were measured by ELISA. Hypoxia was induced in primary human retinal capillary endothelial cells (HRCEC) and mouse brain endothelial cells (MBEC) by CoCl2. Levels of SDF-1 and hypoxia-inducible factor 1 alpha (HIF-1α) were measured by Western blotting.
RESULTS
Fenofibric acid and overexpression of PPARα attenuated the increase of circulating and retinal EPC, correlating with suppressed retinal NV in OIR mice at P17. The PPARα knockout enhanced the OIR-induced increase of circulating and retinal EPC. Fenofibric acid decreased retinal HIF-1α and SDF-1 levels as well as serum SDF-1 levels in the OIR model. In HRCEC, PPARα inhibited HIF-1α nuclear translocation and SDF-1 overexpression induced by hypoxia. Further, MBEC from PPARα(-/-) mice showed more prominent activation of HIF-1α and overexpression of SDF-1 induced by hypoxia, compared with the wild-type (WT) MBEC. PPARα failed to block SDF-1 overexpression induced by a constitutively active mutant of HIF-1α, suggesting that regulation of SDF-1 by PPARα was through blockade of HIF-1α activation.
CONCLUSIONS
Peroxisome proliferator-activated receptor alpha suppresses ischemia-induced EPC mobilization and homing through inhibition of the HIF-1α/SDF-1 pathway. This represents a novel molecular mechanism for PPARα's antiangiogenic effects.
目的
过氧化物酶体增殖物激活受体 α（PPARα）的抗血管生成机制尚不完全清楚。已知内皮祖细胞（EPC）参与新生血管形成（NV）。本研究旨在探讨 PPARα 是否在视网膜 NV 期间调节 EPC。
方法
通过氧诱导的视网膜病变（OIR）诱导视网膜 NV。用 PPARα 激动剂非诺贝特酸（FA）或表达 PPARα 的腺病毒（Ad-PPARα）经腹腔注射 OIR 小鼠。通过流式细胞术定量循环和视网膜 EPC。通过 ELISA 测量血清基质细胞衍生因子 1（SDF-1）水平。用 CoCl2 诱导原代人视网膜毛细血管内皮细胞（HRCEC）和小鼠脑内皮细胞（MBEC）缺氧。通过 Western blot 测量 SDF-1 和缺氧诱导因子 1α（HIF-1α）的水平。
结果
非诺贝特酸和过表达 PPARα 减弱了循环和视网膜 EPC 的增加，与 P17 时 OIR 小鼠视网膜 NV 抑制相关。PPARα 基因敲除增强了 OIR 诱导的循环和视网膜 EPC 的增加。非诺贝特酸降低了 OIR 模型中的视网膜 HIF-1α 和 SDF-1 水平以及血清 SDF-1 水平。在 HRCEC 中，PPARα 抑制了缺氧诱导的 HIF-1α 核转位和 SDF-1 过表达。此外，与野生型（WT）MBEC 相比，PPARα（-/-）小鼠的 MBEC 显示出更明显的 HIF-1α 激活和缺氧诱导的 SDF-1 过表达。PPARα 未能阻断由 HIF-1α 组成型激活突变体诱导的 SDF-1 过表达，表明 PPARα 对 SDF-1 的调节是通过阻断 HIF-1α 激活。
结论
过氧化物酶体增殖物激活受体 α 通过抑制 HIF-1α/SDF-1 通路抑制缺血诱导的 EPC 动员和归巢。这代表了 PPARα 抗血管生成作用的新分子机制。
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