Lai, Yen-ChunYen-ChunLaiPan, Kuan-TingKuan-TingPanChang, Gao-FongGao-FongChangHsu, Chia-HaoChia-HaoHsuKhoo, Kay-HooiKay-HooiKhooHung, Chen-HsiungChen-HsiungHungJiang, Yun-JinYun-JinJiangHo, Feng-MingFeng-MingHoMeng, Tzu-ChingTzu-ChingMeng2012-10-192018-07-062012-10-192018-07-062011http://ntur.lib.ntu.edu.tw//handle/246246/243287Rationale: 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. Conclusions: These results are the first to demonstrate that nitrite plays a critical role in the protection of endothelial barrier function against hypoxic insult. Our findings show that nitrite holds great potential for the treatment of diseases associated with hypoxia-induced disorder of vascular homeostasis. ? 2011 American Heart Association, Inc.en-USCaspase-3; Endothelial barrier dysfunction; Hypoxia; Nitrite; NO[SDGs]SDG3beta catenin; caspase 3; nitrate; nitric oxide; nitrite; nitrite reductase; vascular endothelial cadherin; animal cell; animal experiment; animal tissue; article; blood vessel; cell junction; cell membrane permeability; controlled study; denitrosylation; embryo; endothelial dysfunction; enzyme activation; enzyme active site; enzyme inactivation; experimental model; homeostasis; human; human cell; hypoxia; nitrosylation; nonhuman; priority journal; protein cleavage; umbilical vein endothelial cell; vascular endothelium; zebra fish; Adherens Junctions; Animals; Anoxia; Antigens, CD; beta Catenin; Cadherins; Caspase 3; Cattle; Cell Membrane Permeability; Cells, Cultured; Endothelium, Vascular; Homeostasis; Humans; Mice; Models, Animal; Nitric Oxide; Nitrites; Zebrafishjournal article10.1161/CIRCRESAHA.111.256479http://ntur.lib.ntu.edu.tw/bitstream/246246/243287/-1/17.pdf