Abstract
Although tissue injury and inflammation are considered essential for the induction of angiogenesis, the molecular controls of this cascade are mostly unknown. Here we show that a macrophage-derived peptide, PR39, inhibited the ubiquitin-proteasome-dependent degradation of hypoxia-inducible factor-1alpha protein, resulting in accelerated formation of vascular structures in vitro and increased myocardial vasculature in mice. For the latter, coronary flow studies demonstrated that PR39-induced angiogenesis resulted in the production of functional blood vessels. These findings show that PR39 and related compounds can be used as potent inductors of angiogenesis, and that selective inhibition of hypoxia-inducible factor-1alpha degradation may underlie the mechanism of inflammation-induced angiogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antimicrobial Cationic Peptides*
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Aorta
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Capillaries / drug effects
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Capillaries / physiology
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Cattle
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Cell Hypoxia
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Cells, Cultured
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Coronary Vessels / drug effects
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Cysteine Endopeptidases / metabolism
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DNA-Binding Proteins / metabolism*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / physiology*
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Heart / physiology
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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In Vitro Techniques
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Macrophages / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Multienzyme Complexes / metabolism
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Myocardial Infarction / pathology
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Myocardial Infarction / physiopathology
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Myocardial Ischemia / pathology
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Myocardial Ischemia / physiopathology*
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Neovascularization, Physiologic / physiology*
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Nuclear Proteins / metabolism*
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Peptides / genetics
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Peptides / pharmacology
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Peptides / physiology*
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Proteasome Endopeptidase Complex
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Recombinant Proteins / metabolism
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Swine
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Transcription Factors / metabolism
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Ubiquitins / metabolism
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Umbilical Veins
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von Willebrand Factor / genetics
Substances
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Antimicrobial Cationic Peptides
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DNA-Binding Proteins
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HIF1A protein, human
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Multienzyme Complexes
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Nuclear Proteins
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Peptides
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Recombinant Proteins
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Transcription Factors
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Ubiquitins
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von Willebrand Factor
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PR 39
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex