학술논문
The Phosphatase SHP-2 Activates HIF-1α in Wounds In Vivo by Inhibition of 26S Proteasome Activity.
Document Type
Academic Journal
Author
Heun Y; Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 27, 81377 Munich, Germany. yvonn.heun@gmx.de.; Biomedical Center, Ludwig-Maximilians-University, Großhaderner Str. 9, 82152 Planegg, Germany. yvonn.heun@gmx.de.; Grundler Groterhorst K; Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 27, 81377 Munich, Germany. gruendler.k@gmail.com.; Medizinische Klinik und Poliklinik I, Klinikum der Universität München, LMU, Marchioninistrasse 15, 81377 Munich, Germany. gruendler.k@gmail.com.; Pogoda K; Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 27, 81377 Munich, Germany. kristin.pogoda@lrz.uni-muenchen.de.; Biomedical Center, Ludwig-Maximilians-University, Großhaderner Str. 9, 82152 Planegg, Germany. kristin.pogoda@lrz.uni-muenchen.de.; Kraemer BF; Medizinische Klinik und Poliklinik I, Klinikum der Universität München, LMU, Marchioninistrasse 15, 81377 Munich, Germany. B.F.K@gmx.de.; Pfeifer A; Institute of Pharmacology and Toxicology, Biomedical Center University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany. alexander.pfeifer@uni-bonn.de.; Pohl U; Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 27, 81377 Munich, Germany. upohl@lmu.de.; Biomedical Center, Ludwig-Maximilians-University, Großhaderner Str. 9, 82152 Planegg, Germany. upohl@lmu.de.; Mannell H; Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 27, 81377 Munich, Germany. hanna.mannell@med.uni-muenchen.de.; Biomedical Center, Ludwig-Maximilians-University, Großhaderner Str. 9, 82152 Planegg, Germany. hanna.mannell@med.uni-muenchen.de.; Hospital Pharmacy, Klinikum der Universität München, LMU, Marchioninistrasse 15, 81377 Munich, Germany. hanna.mannell@med.uni-muenchen.de.
Source
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
Subject
Language
English
Abstract
Vascular remodeling and angiogenesis are required to improve the perfusion of ischemic tissues. The hypoxic environment, induced by ischemia, is a potent stimulus for hypoxia inducible factor 1α (HIF-1α) upregulation and activation, which induce pro-angiogenic gene expression. We previously showed that the tyrosine phosphatase SHP-2 drives hypoxia mediated HIF-1α upregulation via inhibition of the proteasomal pathway, resulting in revascularization of wounds in vivo. However, it is still unknown if SHP-2 mediates HIF-1α upregulation by affecting 26S proteasome activity and how the proteasome is regulated upon hypoxia. Using a reporter construct containing the oxygen-dependent degradation (ODD) domain of HIF-1α and a fluorogenic proteasome substrate in combination with SHP-2 mutant constructs, we show that SHP-2 inhibits the 26S proteasome activity in endothelial cells under hypoxic conditions in vitro via Src kinase/p38 mitogen-activated protein kinase (MAPK) signalling. Moreover, the simultaneous expression of constitutively active SHP-2 (E76A) and inactive SHP-2 (CS) in separate hypoxic wounds in the mice dorsal skin fold chamber by localized magnetic nanoparticle-assisted lentiviral transduction showed specific regulation of proteasome activity in vivo. Thus, we identified a new additional mechanism of SHP-2 mediated HIF-1α upregulation and proteasome activity, being functionally important for revascularization of wounds in vivo. SHP-2 may therefore constitute a potential novel therapeutic target for the induction of angiogenesis in ischemic vascular disease.