Thrombin upregulates tissue transglutaminase in endothelial cells - A potential role for tissue transglutaminase in stability of atherosclerotic plaque

Atherosclerosis is characterized by thickening of the vessel wall, smooth m uscle cell proliferation, macrophage infiltration, and deposition of a fibr in network. Transglutaminases are a family of enzymes catalyzing the format ion of stable covalent cross-links between proteins. Here, we show that tis sue transglutaminase (tTG) synthesis by human umbilical vein endothelial ce lls is upregulated by thrombin, the serine protease that causes fibrin form ation and many cellular inflammatory effects. Thrombin upregulated tTG 2-fo ld at the mRNA and protein level. Cellular cross-linking activity was incre ased to an even greater extent; antibody to tTG neutralized the increased a ctivity. The effect on tTG expression required active thrombin and was medi ated mainly through protease-activated receptor-1, a thrombin receptor. Inc reased tTG antigen and activity were evident in human umbilical vein endoth elial cells and extracellular matrix in situ. Thrombin treatment also led t o a cellular redistribution of tTG. Normal vessel wall stained positively f or tTG in the smooth muscle cells and in the subendothelium. The intensity of staining increased in vessel walls with plaque, where there was a striki ng increase in tTG in the smooth muscle cells immediately below the plaque. These studies indicate a role for tTG in the stabilization of atherosclero tic plaques and suggest that its local expression can be controlled by thro mbin.