Involvement of thrombin/thrombin receptor signaling in the development of vascular remodeling

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We have investigated in the signal transduction from thrombin receptor, PAR-1 and its role in the development in atherosclerosis/vascular remodeling and thrombosis.We identified as follows:1. The activation of PAR-1 by thrombin causes the expression of cell adhesion molecules(CAM), inflammatory cytokines, tissue factor, and PAI-1. This may play some roles in the development in atherosclerosis/vascular remodeling and thrombosis.2.Thrombin activates PAR-1, and causes the activation of NF-ィイD2κィエD2B through MAP kinase pathway, resulting the proliferation of vascular smooth muscle cells.3. On the other hand, PAR-1 activation causes apoptosis through caspase cascade.4.Furthermore, we showed the signaling from PAR-1 activates histone acetyltransferase(HAT) with CBP/p300 activation in the cultured vascular smooth muscle cells. This causes accumulation of acetylated proteins at lysine residue, named as hyper-nuclear acetylation(HNA).5. We showed HNA in atherosclerotic plaque in human cororary artery.Based on these data, we conclude the signaling from thrombin receptor activates NF-ィイD2κィエD2B and CBP/p300 through MAP kinase cascade. This may cause proliferation, activation, and/or apoptosis in vascular smooth muslce cells, and play some roles for the development in vascular remodeling/restenosis and atherosclerosis/thrombosis.