C/EBP Homologous Protein-10 (CHOP-10) Limits Postnatal Neovascularization Through Control of Endothelial Nitric Oxide Synthase Gene Expression
| Autor: | Bhama Ramkhelawon, Adèle Richart, Patricia Rueda, Micheline Duriez, Yasmine Zouggari, Christophe Heymes, Céline Loinard, Fernando Arenzana-Seisdedos, Masataka Mori, Dominique Charue, Jean-Sébastien Silvestre, José Vilar, A. Récalde, Bernard I. Levy, Clément Cochain |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Transcriptional Activation
medicine.medical_specialty Nitric Oxide Synthase Type III genetic structures Angiogenesis CHOP Gene Expression Regulation Enzymologic Diabetes Mellitus Experimental Neovascularization Mice Vasculogenesis hemic and lymphatic diseases Physiology (medical) Internal medicine Gene expression medicine Animals Humans Nuclear protein Cells Cultured Mice Knockout Neovascularization Pathologic biology eye diseases Up-Regulation Cell biology Femoral Artery Mice Inbred C57BL Nitric oxide synthase Endocrinology Animals Newborn biology.protein medicine.symptom Cardiology and Cardiovascular Medicine Transcription Factor CHOP Protein C Protein Binding medicine.drug |
| Zdroj: | Circulation. 125:1014-1026 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.111.041830 |
| Popis: | Background— C/EBP homologous protein-10 (CHOP-10) is a novel developmentally regulated nuclear protein that emerges as a critical transcriptional integrator among pathways regulating differentiation, proliferation, and survival. In the present study, we analyzed the role of CHOP-10 in postnatal neovascularization. Methods and Results— Ischemia was induced by right femoral artery ligation in wild-type and CHOP-10 −/− mice. In capillary structure of skeletal muscle, CHOP-10 mRNA and protein levels were upregulated by ischemia and diabetes mellitus. Angiographic score, capillary density, and foot perfusion were increased in CHOP-10 −/− mice compared with wild-type mice. This effect was associated with a reduction in apoptosis and an upregulation of endothelial nitric oxide synthase (eNOS) levels in ischemic legs of CHOP-10 −/− mice compared with wild-type mice. In agreement with these results, eNOS mRNA and protein levels were significantly upregulated in CHOP-10 short interfering RNA–transfected human endothelial cells, whereas overexpression of CHOP-10 inhibited basal transcriptional activation of the eNOS promoter. Using a chromatin immunoprecipitation assay, we also showed that CHOP-10 was bound to the eNOS promoter. Interestingly, enhanced postischemic neovascularization in CHOP-10 −/− mice was fully blunted in CHOP-10/eNOS double-knockout animals. Finally, we showed that induction of diabetes mellitus is associated with a marked upregulation of CHOP-10 that substantially inhibited postischemic neovascularization. Conclusions— This study identifies CHOP-10 as an important transcription factor modulating vessel formation and maturation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|