Regulation of VEGF-induced endothelial cell PAF synthesis: role of p42/44 MAPK, p38 MAPK and PI3K pathways

1. Vascular endothelial growth factor (VEGF) is a potent angiogenic and inflammatory mediator. We have recently shown that this latter effect requires the activation of Flk-1 receptor and subsequent endothelial cell (EC) PAF synthesis. However, the intracellular events that regulate EC PAF synthesis upon Flk-1 stimulation by VEGF remain to be elucidated. 2. Using specific inhibitors and Western blot analysis, we herein report that in bovine aortic endothelial cells (BAEC), VEGF induces the synthesis of PAF through the cascade activation of Flk-1 receptor, phospholipase Cγ (PLCγ), protein kinase C (PKC) and p42/44 mitogen-activated protein kinases (MAPK). 3. Moreover, we demonstrate that VEGF-mediated PAF synthesis requires the activation of p38 MAPK, likely by directing the conversion of lyso-PAF to PAF. 4. Interestingly, we observed that VEGF also promoted the activation of the phosphatidyl inositol-3-phosphate kinase (PI3K) pathway, and that its blockade potentiated PAF synthesis following a VEGF treatment. Consequently, it appears that the PI3K pathway acts as a negative regulator of EC PAF synthesis. 5. Taken together, these results allow a better understanding of the intracellular events activated upon EC stimulation by VEGF, and shed a new light on the mechanisms by which VEGF induces PAF synthesis

SUCRALFATE, RANITIDINE AND NO TREATMENT IN GASTRIC-ULCER MANAGEMENT - A MULTICENTER, PROSPECTIVE, RANDOMIZED, 24-MONTH FOLLOW-UP WITH A STUDY OF RISK-FACTORS OF RELAPSE

This multicenter, prospective, randomized, open, long-term study compares sucralfate (2 g daily) with ranitidine (150 mg daily) and no treatment in gastric ulcer (GU). We report the results of the second year of a scheduled 3-year follow-up, the outcome of the 1st year has been reported earlier. The 24-month follow-up was completed by 142 patients who were continuously either treated with the drug randomly assigned at the beginning of the study or left untreated (i.e. 32 patients took 150 mg ranitidine at bedtime, 29 took 1 g sucralfate twice daily and 81 were left untreated, 23 of whom came from the ranitidine group, 19 from the sucralfate group and 39 from the untreated group). Seven patients dropped out and 26 subjects relapsed (5 under ranitidine, 4 under sucralfate and 17 untreated cases). Ranitidine versus previous ranitidine, sucralfate versus previous sucralfate and each one versus no treatment showed comparable relapse rates. An additional study, using Cox's models, showed that three variables have a significant correlation with relapse during the 1st year of follow-up: therapy carried out (p = 0.0025), symptoms (p = 0.0047) and family history of ulcer (p = 0.0392). In conclusion, both ranitidine 150 mg and sucralfate 2 g proved effective in reducing GU relapse as compared with no treatment, an effect which does not seem to persist during the 2nd year of therapy, when the 'no treatment' option may be taken into account