Homocysteineâinduced decrease in endothelinâ1 production is initiated at the extracellular level and involves oxidative products
2001
Drunat, Séverine | Moatti, Nicole | Paul, Jean-Louis | Cogny, Anne | Benoit, MarieâOdile | Demuth, Karine
The increased cardiovascular risk associated with hyperhomocysteinemia has been partly related to homocysteine (Hcy)âinduced endothelial cell dysfunction. However, the intra or extracellular starting point of the interaction between Hcy and endothelial cells, leading to cellular dysfunction, has not yet been identified. We investigated the effects of both intracellular and extracellular Hcy accumulation on endothelinâ1 (ETâ1) synthesis by cultured human endothelial cells. Incubation of cultures with methionine (1.0âmmol·L−1) for 2âh induced a slight increase in cellular Hcy content but no change in ETâ1 production. Incubation of cells with Hcy (0.2âmmol·L−1) led to a significant fall in ETâ1 generation, accompanied by a significant increase in cellular Hcy content. Addition of the aminoâacid transport system L substrate 2âaminoâ2ânorbornane carboxylic acid had no effect on the Hcyâinduced decrease in ETâ1 production but significantly inhibited the Hcyâinduced increase in the cellular Hcy content. Incubation of cells with a lower Hcy concentration (0.05âmmol·L−1) also reduced ETâ1 production without increasing the cellular Hcy content. Coâincubation with extracellular freeâradical inhibitors (superoxide dismutase, catalase and mannitol) markedly reduced the effect of Hcy on ETâ1 production. Thus, it is extracellular Hcy accumulation that triggers the decrease in ETâ1 production by endothelial cells through oxidative products.
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