CHOP-10 Limits Postnatal Neovascularization Through the Control of eNOS Gene Expression
Background—CHOP-10 is a novel developmentally regulated nuclear protein that emerges as critical transcriptional integrator among pathways regulating differentiation, proliferation and survival. Here, we analyzed the role of CHOP-10 in postnatal neovascularization.
Methods and Results—Ischemia was induced by right femoral artery ligation in wild-type (WT) and CHOP-10-/- mice. In capillary structure of skeletal muscle, CHOP-10 mRNA and protein levels were upregulated by ischemia and diabetes. Angiographic score, capillary density and foot perfusion were increased in CHOP-10-/-mice compared to WT. This effect was associated with a reduction in apoptosis and an upregulation of eNOS levels in ischemic legs of CHOP-10-/-mice compared to WT. In line with these results, eNOS mRNA and protein levels were significantly upregulated in CHOP-10 siRNA-transfected human endothelial cells whereas overexpression of CHOP-10 inhibited basal transcriptional activation of the eNOS promoter. Using chromatin immunoprecipitation assay, we also showed that CHOP-10 bound to the eNOS promoter. Interestingly, enhanced post-ischemic neovascularization in CHOP-10-/-mice was fully blunted in CHOP-10/eNOS double knock out animals. Finally, we showed that induction of diabetes is associated with a marked upregulation of CHOP-10 that substantially inhibited post-ischemic neovascularization.
Conclusions—This study identifies CHOP-10 as an important transcription factor modulating vessel formation and maturation.
- Received May 5, 2011.
- Accepted January 13, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited