title: PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-γ to increase surface FasL.
abstract: Pigment epithelial-derived factor (PEDF) is a potent anti-angiogenic factor whose effects are partially mediated through the induction of endothelial cell apoptosis. However, the underlying mechanism for PEDF and the functional PEDF peptides 34-mer and 44-mer to inhibit angiogenesis in the heart has not been fully established. In the present study, by constructing adult Sprague-Dawley rat models of acute myocardial infarction (AMI) and in vitro myocardial angiogenesis, we showed that PEDF and 34-mer markedly inhibits angiogenesis by selectively inducing tip cells apoptosis rather than quiescent cells. Peptide 44-mer on the other hand exhibits no such effects. Next, we identified Fas death pathway as essential downstream regulators of PEDF and 34-mer activities in inhibiting angiogenesis. By using peroxisome proliferator-activated receptor γ (PPAR-γ) siRNA and PPAR-γ inhibitor, GW9662, we found the effects of PEDF and 34-mer were extensively blocked. These data suggest that PEDF and 34-mer inhibit angiogenesis via inducing tip cells apoptosis at least by means of up-regulating PPAR-γ to increase surface FasL in the ischemic heart, which might be a novel mechanism to understanding cardiac angiogenesis after AMI.
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221006, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221006, China.
authors.forename: Tengteng
authors.initials: T
authors.lastname: Wei
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221006, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221006, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221006, China.
authors.forename: Huazhu
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221006, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Biology, Xuzhou Medical College, Xuzhou, 221004, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhuang
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221006, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Biology, Xuzhou Medical College, Xuzhou, 221004, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221006, China. zhang_zhongming@xzmc.edu.cn.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biology, Xuzhou Medical College, Xuzhou, 221004, China. dhy@xzmc.edu.cn.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Dong
mesh_terms: D000595:Amino Acid Sequence; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000813:Anilides; D005136:Eye Proteins; D053222:Fas Ligand Protein; D009414:Nerve Growth Factors; D047495:PPAR gamma; D010455:Peptides; D034741:RNA, Small Interfering; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C457499:2-chloro-5-nitrobenzanilide; C505662:Faslg protein, rat
keywords: 34mer; Fas/FasL; PPAR-γ; Pigment epithelium-derived factor (PEDF); Tip cell