| First Author | Guo J | Year | 2015 |
| Journal | Cardiovasc Res | Volume | 105 |
| Issue | 3 | Pages | 383-93 |
| PubMed ID | 25589425 | Mgi Jnum | J:258500 |
| Mgi Id | MGI:6140430 | Doi | 10.1093/cvr/cvv010 |
| Citation | Guo J, et al. (2015) A secreted protein (Canopy 2, CNPY2) enhances angiogenesis and promotes smooth muscle cell migration and proliferation. Cardiovasc Res 105(3):383-93 |
| abstractText | AIMS: Ischaemic heart disease is a leading cause of mortality. After ischaemic injury, tissue hypoxia induces the activity of angiogenic factors that promote revascularization. Increased understanding of hypoxia-responsive genes and their role in angiogenesis will lead to new therapies for ischaemic injury. We delineated the function of Canopy 2 (CNPY2), a newly discovered, hypoxia-regulated gene. METHODS AND RESULTS: We found CNPY2 in a screen for genes induced by low oxygen in human smooth muscle cells (SMCs). CNPY2 protein co-localized with the endoplasmic reticulum and the Golgi. Treatment with Brefeldin A, which destroys Golgi stacks, resulted in CNPY2 accumulation in the endoplasmic reticulum. Secreted CNPY2 was detected in the blood of healthy mice and humans, and the medium of cultured SMCs. SMCs under hypoxia or treated with a prolyl-4-hydroxylase inhibitor stabilized HIF-1alpha protein and up-regulated CNPY2, while CNPY2 induction was lost after HIF-1alpha silencing. Chromatin immunoprecipitation demonstrated that HIF-1alpha binds to a hypoxia response element (HRE-1157) upstream of the human CNPY2 promoter, which was verified by a luciferase reporter driven by HRE-1157-containing constructs. CNPY2 stimulation activated Cdc42, PAK1, and FAK in SMCs, resulting in enhanced proliferation and migration in vitro, and dramatic aortic ring sprouting ex vivo. CNPY2 significantly increased revascularization of the mouse retina after reperfusion injury. CONCLUSIONS: CNPY2 is a HIF-1alpha-regulated, secreted angiogenic growth factor that promotes SMC migration, proliferation, and tissue revascularization. This new target may have a broader profile than currently available proteins. |
