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PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-γ to increase surface FasL

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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.

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Acknowledgments

This work was supported by grants from the National Nature Science Foundation of China (81400227), the National Nature Science Foundation of China (81270173) and Natural Science Foundation for colleges and universities in Jiangsu Province (14KJB320026).

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    Authors and Affiliations

    1. Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221006, China

      Hao Zhang, Tengteng Wei, Xia Jiang, Zhimin Li, Huazhu Cui, Jiajun Pan, Teng Sun & Zhongming Zhang

    2. Department of Biology, Xuzhou Medical College, Xuzhou, 221004, China

      Wei Zhuang, Zhiwei Liu & Hongyan Dong

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    1. Hao Zhang
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    Correspondence to Zhongming Zhang or Hongyan Dong.

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    Hao Zhang, Tengteng Wei, and Xia Jiang have contributed equally to this work.

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    Zhang, H., Wei, T., Jiang, X. et al. PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-γ to increase surface FasL. Apoptosis 21, 60–68 (2016). https://doi.org/10.1007/s10495-015-1186-1

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