Ischemia-induced angiogenesis is impaired in aminopeptidase A deficient mice via down-regulation of HIF-1α.

Abstract

Aminopeptidase A (APA; EC 3.4.11.7) is a transmembrane metalloprotease with several functions in tumor angiogenesis. To investigate the role of APA in the process of ischemia-induced angiogenesis, we evaluated the cellular angiogenic responses under hypoxic conditions and the process of perfusion recovery in the hindlimb ischemia model of APA-deficient (APA-KO; C57Bl6/J strain) mice. Western blotting of endothelial cells (ECs) isolated from the aorta of APA-KO mice revealed that the accumulation of hypoxia-inducible factor-1α (HIF-1α) protein in response to hypoxic challenge was blunted. Regarding the proteasomal ubiquitination, a proteasome inhibitor MG-132 restored the reduced accumulation of HIF-1α in ECs from APA-KO mice similar to control mice under hypoxic conditions. These were associated with decreased growth factor secretion and capillary formation in APA-KO mice. In the hindlimb ischemia model, perfusion recovery in APA-KO mice was decreased in accordance with a significantly lower capillary density at 2weeks. Regarding vasculogenesis, no differences were observed in cell populations and distribution patterns between wild type and APA-KO mice in relation to endothelial progenitor cells. Our results suggested that Ischemia-induced angiogenesis is impaired in APA-KO mice partly through decreased HIF-1α stability by proteasomal degradation and subsequent suppression of HIF-1α-driven target protein expression such as growth factors. APA is a functional target for ischemia-induced angiogenesis.

• Authors: Ryuji Kubota, Yasushi Numaguchi, Masakazu Ishii, Manabu Niwa, Kenji Okumura, Keiji Naruse, Toyoaki Murohara
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 402 Issue 2 Pg. 396-401 (Nov 12 2010) ISSN: 1090-2104 [Electronic] United States
• PMID: 20946870 (Publication Type: Journal Article)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Glutamyl Aminopeptidase

Topics

• Animals
• Cell Hypoxia
• Down-Regulation
• Glutamyl Aminopeptidase (genetics, metabolism)
• Hindlimb (blood supply)
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Ischemia (complications)
• Mice
• Mice, Knockout
• Neovascularization, Pathologic (enzymology, etiology, genetics)