Transforming growth factor–β1 induces apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase***

Abstract Background. Vascular endothelial cell apoptosis is central in atherosclerosis and intimal hyperplasia. Transforming growth factor (TGF)-β1 induces endothelial cell apoptosis through unidentified mechanism(s). Although TGF-β1 signals through the Smad proteins, in some nonendothelial cell types it also activates the mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK [p38 MAPK ]). p38 MAPK relays apoptotic signals in several cell types. We hypothesized that TGF-β1 activates endothelial cell MAPKs and induces apoptosis through p38 MAPK activation. Methods. Human umbilical vein or bovine capillary endothelial cells were incubated with TGF-β1 for 0.5 to 12 hours. MAPK activation was characterized by Western blotting with antibodies to phosphorylated extracellular signal-regulated kinase 1/2, p38 MAPK , or c-Jun N-terminal kinases 1/2. To study apoptosis, extracts of cells incubated with TGF-β1 for 6 hours with or without MAPK inhibitors were characterized by Western blotting analysis of poly (ADP-Ribose) polymerase degradation. Results. TGF-β1 induced p38 MAPK , extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase 1/2 activation and increased apoptosis. Inhibition of p38 MAPK significantly reduced TGF-β1-induced apoptosis. In contrast, inhibition of other signaling pathways was ineffective. Conclusions. TGF-β1 induces endothelial cell apoptosis through p38 MAPK activation. Because TGF-β1 is upregulated in vascular remodeling, p38 MAPK is a potential target to prevent endothelial cell apoptosis during this process. (Surgery 2002;132:173-9.)