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PPAR? regulates mobilization and homing of endothelial progenitor cells through the HIF-1?/SDF-1 pathway.

ABSTRACT: The mechanism for the antiangiogenic activity of peroxisome proliferator-activated receptor alpha (PPAR?) remains incompletely understood. Endothelial progenitor cells (EPC) are known to participate in neovascularization (NV). The purpose of this study was to investigate whether PPAR? regulates EPC during retinal NV.Retinal NV was induced by oxygen-induced retinopathy (OIR). Mice with OIR were injected intraperitoneally with the PPAR? agonist fenofibric acid (FA) or with adenovirus expressing PPAR? (Ad-PPAR?). 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-1?) were measured by Western blotting.Fenofibric acid and overexpression of PPAR? attenuated the increase of circulating and retinal EPC, correlating with suppressed retinal NV in OIR mice at P17. The PPAR? knockout enhanced the OIR-induced increase of circulating and retinal EPC. Fenofibric acid decreased retinal HIF-1? and SDF-1 levels as well as serum SDF-1 levels in the OIR model. In HRCEC, PPAR? inhibited HIF-1? nuclear translocation and SDF-1 overexpression induced by hypoxia. Further, MBEC from PPAR?(-/-) mice showed more prominent activation of HIF-1? and overexpression of SDF-1 induced by hypoxia, compared with the wild-type (WT) MBEC. PPAR? failed to block SDF-1 overexpression induced by a constitutively active mutant of HIF-1?, suggesting that regulation of SDF-1 by PPAR? was through blockade of HIF-1? activation.Peroxisome proliferator-activated receptor alpha suppresses ischemia-induced EPC mobilization and homing through inhibition of the HIF-1?/SDF-1 pathway. This represents a novel molecular mechanism for PPAR?'s antiangiogenic effects.

SUBMITTER: Wang Z

PROVIDER: S-EPMC4064689 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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PPARα regulates mobilization and homing of endothelial progenitor cells through the HIF-1α/SDF-1 pathway.

Wang Zhongxiao Z Moran Elizabeth E Ding Lexi L Cheng Rui R Xu Xun X Ma Jian-xing JX

Investigative ophthalmology & visual science 20140520 6

<h4>Purpose</h4>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.<h4>Methods</h4>Retinal NV was induced by oxygen-induced retinopathy (OIR). Mice with OIR were injected intraperitoneally with the PPARα agonist fenofibric acid (FA) ...[more]

PMID: 24845641

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Project description:BackgroundThe control of endothelial progenitor cells (CD133+/CD34+ EPCs) migrating from bone marrow to peripheral blood is not completely understood. Emerging evidence suggests that stromal cell-derived factor-1α (SDF-1α) mediates egression of EPCs from bone marrow, while the hypoxia inducible factor (HIF) transcriptional system regulates SDF-1α expression. Our study aimed to investigate the time course of circulating CD133+/CD34+ EPCs and its correlation with the expression of HIF-1α protein and SDF-1α in postoperative laparoscopic abdominal septic patients.MethodsPostoperative patients were divided in control (C group) and septic group (S group) operated immediately after the diagnosis of sepsis/septic shock. Blood samples were collected at baseline (0), 1, 3 and 7 postoperative days for CD133+/CD34+ EPCs count expressing or not the HIF-1α and SDF-1α analysis.ResultsThirty-two patients in S group and 39 in C group were analyzed. In C group CD133+/CD34+ EPCs count remained stable throughout the study period, increasing on day 7 (173 [0-421] /μl vs baseline: P = 0.04; vs day 1: P = 0.002). In S group CD133+/CD34+ EPCs count levels were higher on day 3 (vs day 1: P = 0.006 and day 7: P = 0.026). HIF-1α expressing CD133+/CD34+ EPCs count decreased on day 1 as compared with the other days in C group (day 0 vs 1: P = 0.003, days 3 and 7 vs 1: P = 0.008), while it was 321 [0-1418] /μl on day 3 (vs day 1; P = 0.004), and 400 [0-587] /μl on day 7 in S group. SDF-1α levels were higher not only on baseline but also on postoperative day 1 in S vs C group (219 [124-337] pg/ml vs 35 [27-325] pg/ml, respectively; P = 0.01).ConclusionOur results indicate that sepsis in abdominal laparoscopic patients might constitute an additional trigger of the EPCs mobilization as compared with non-septic surgical patients. A larger mobilization of CD133+/CD34+ EPCs, preceded by enhanced plasmatic SDF-1α, occurs in septic surgical patients regardless of HIF-1α expression therein.Trial registrationClinicalTrials.gov no. NCT02589535 . Registered 28 October 2015.

Project description:Ischemic heart disease (IHD) is one of the main focuses in today's healthcare due to its implications and complications, and it is predicted to be increasing in prevalence due to the ageing population. Although the conventional pharmacological and interventional methods for the treatment of IHD presents with success in the clinical setting, the long-term complications of cardiac insufficiency are on a continual incline as a result of post-infarction remodeling of the cardiac tissue. The migration and involvement of stem cells to the cardiac muscle, followed by differentiation into cardiac myocytes, has been proven to be the natural process, though at a slow rate. SDF-1α is a novel candidate to mobilize stem cells homing to the ischemic heart. Endogenous SDF-1α levels are elevated after myocardial infarction, but their presence gradually decreases after approximately seven days. Additional administration of SDF-1α-releasing microspheres could be a tool for the extension of the time the stem cells are in the cardiac tissue after myocardial infarction. This, in turn, could constitute a novel therapy for more efficient regeneration of the heart muscle after injury. Through this practical study, it has been shown that the controlled release of SDF-1α from biodegradable microspheres into the pericardial sac fourteen days after myocardial infarction increases the concentration of exogenous SDF-1α, which persists in the tissue much longer than the level of endogenous SDF-1α. In addition, administration of SDF-1α-releasing microspheres increased the expression of the factors potentially involved in the involvement and retention of myocardial stem cells, which constitutes vascular endothelial growth factor A (VEGFA), stem cell factor (SCF), and vascular cell adhesion molecules (VCAMs) at the site of damaged tissue. This exhibits the possibility of combating the basic limitations of cell therapy, including ineffective stem cell implantation and the ability to induce the migration of endogenous stem cells to the ischemic cardiac tissue and promote heart repair.

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PPAR? regulates mobilization and homing of endothelial progenitor cells through the HIF-1?/SDF-1 pathway.

Publications

PPARα regulates mobilization and homing of endothelial progenitor cells through the HIF-1α/SDF-1 pathway.

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