|ZFIN ID: ZDB-PUB-111111-12|
|Source:||Circulation research 109(12): 1375-86 (Journal)|
|Registered Authors:||Jiang, Yun-Jin|
|Keywords:||nitrite, NO, caspase-3, hypoxia, endothelial barrier dysfunction|
|PubMed:||22021929 Full text @ Circ. Res.|
Rationale: Hypoxia is a significant perturbation that exacerbates endothelial barrier dysfunction, contributing to the disruption of vascular homeostasis and the development of various diseases such as atherosclerosis and metastasis of tumors. To date, it is not known what strategy might be used to counter the effect of hypoxia on endothelial permeability.
Objective: This study investigated the role of nitrite in regulating vascular integrity under hypoxic conditions.
Methods and Results: We found denitrosylation and the resulting activation of caspase-3 to be critical for hypoxia-induced endothelial permeability. Nitrite treatment led to S-nitrosylation and the inactivation of caspase-3, suppressing the barrier dysfunction of endothelia caused by hypoxia. This process required the conversion of nitrite to bioactive nitric oxide in a nitrite reductase-dependent manner. Using primary human umbilical vein endothelial cells as a model, we showed that in the presence of nitrite, the S-nitrosylated and inactivated form of caspase-3 was unable to cleave β-catenin, a key component in the VE-cadherin complex. Therefore, nitrite treatment led to the maintenance of VE-cadherin–mediated adherens junctions under hypoxic conditions. In in vivo experiments using a zebrafish model, nitrite was found to protect blood vessels from hypoxia-induced vascular leakage.