The Mechanism And Function Of Nitrite On Hypoxia-induced Endothelial Barrier Dysfunction

• Main Authors: Lai, Yen-Chun, 賴彥錞
• Other Authors: Meng, Tzu-Ching
• Format: Others
• Language: en_US
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/87810060375664273520

博士 === 國防醫學院 === 生命科學研究所 === 100 === Increased endothelial permeability has been regarded as a key step contributing to hypoxia-associated vascular disorders, 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. This study investigated the role of nitrite in regulating vascular integrity under hypoxic conditions. We found denitrosylation and the resulting activation of caspase-3 to be critical for hypoxia-induced endothelial permeability. Treatment with nitrite results in renitrosylation and the inactivation of caspase-3, thus suppressing the barrier dysfunction of endothelia caused by hypoxia. This process required the conversion of nitrite to bioactive nitric oxide (NO) in a nitrite reductase-dependent manner. Using primary HUVECs as a model, we showed that in the presence of nitrite, the S-nitrosylated and inactivated form of caspase-3 was unable to cleave B-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. Furthermore, using an in vivo zebrafish model, nitrite was found to protect blood vessels from vascular leakage caused by hypoxia. Our findings reveal a molecular basis for the protective effect of nitrite in preventing hypoxia-induced endothelial barrier dysfunction and shed lights on the therapeutic potential of nitrite for the treatment of hypoxia-associated disorders.