Identification of cyclins A1, E1 and vimentin as downstream targets of heme oxygenase-1 in vascular endothelial growth factor-mediated angiogenesis
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Published version
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Author(s)
Type
Journal Article
Abstract
Angiogenesis is an essential physiological process and an important factor in disease
pathogenesis. However, its exploitation as a clinical target has achieved limited success and novel
molecular targets are required. Although heme oxygenase-1 (HO-1) acts downstream of vascular
endothelial growth factor (VEGF) to modulate angiogenesis, knowledge of the mechanisms
involved remains limited. We set out identify novel HO-1 targets involved in angiogenesis. HO-1
depletion attenuated VEGF-induced human endothelial cell (EC) proliferation and tube formation.
The latter response suggested a role for HO-1 in EC migration, and indeed HO-1 siRNA negatively
affected directional migration of EC towards VEGF; a phenotype reversed by HO-1 overexpression.
EC from Hmox1-/- mice behaved similarly. Microarray analysis of HO-1-depleted and
control EC exposed to VEGF identified cyclins A1 and E1 as HO-1 targets. Migrating HO-1-
deficient EC showed increased p27, reduced cyclin A1 and attenuated cyclin-dependent kinase 2
activity. In vivo, cyclin A1 siRNA inhibited VEGF-driven angiogenesis, a response reversed by AdHO-1.
Proteomics identified structural protein vimentin as an additional VEGF-HO-1 target. HO-1
depletion inhibited VEGF-induced calpain activity and vimentin cleavage, while vimentin silencing
attenuated HO-1-driven proliferation. Thus, vimentin and cyclins A1 and E1 represent VEGFactivated
HO-1-dependent targets important for VEGF-driven angiogenesis.
pathogenesis. However, its exploitation as a clinical target has achieved limited success and novel
molecular targets are required. Although heme oxygenase-1 (HO-1) acts downstream of vascular
endothelial growth factor (VEGF) to modulate angiogenesis, knowledge of the mechanisms
involved remains limited. We set out identify novel HO-1 targets involved in angiogenesis. HO-1
depletion attenuated VEGF-induced human endothelial cell (EC) proliferation and tube formation.
The latter response suggested a role for HO-1 in EC migration, and indeed HO-1 siRNA negatively
affected directional migration of EC towards VEGF; a phenotype reversed by HO-1 overexpression.
EC from Hmox1-/- mice behaved similarly. Microarray analysis of HO-1-depleted and
control EC exposed to VEGF identified cyclins A1 and E1 as HO-1 targets. Migrating HO-1-
deficient EC showed increased p27, reduced cyclin A1 and attenuated cyclin-dependent kinase 2
activity. In vivo, cyclin A1 siRNA inhibited VEGF-driven angiogenesis, a response reversed by AdHO-1.
Proteomics identified structural protein vimentin as an additional VEGF-HO-1 target. HO-1
depletion inhibited VEGF-induced calpain activity and vimentin cleavage, while vimentin silencing
attenuated HO-1-driven proliferation. Thus, vimentin and cyclins A1 and E1 represent VEGFactivated
HO-1-dependent targets important for VEGF-driven angiogenesis.
Date Issued
2016-07-08
Date Acceptance
2016-06-17
Citation
Scientific Reports, 2016, 6
ISSN
2045-2322
Publisher
Nature Publishing Group
Journal / Book Title
Scientific Reports
Volume
6
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unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material. To view a copy of this
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Publication Status
Published
Article Number
29417