Transglutaminases Affect Plaque Composition and Size in Regions Exposed to Oscillatory Shear Stress

Transglutaminases (TGs) are involved in macrophage infiltration, and are found in human atherosclerotic lesions. We hypothesized that TGs affect the development of atherosclerotic lesions. Methods A tapering cast was placed around the carotid artery of ApoE−/− mice (n=16), creating a lowered shear stress proximal of the cast (LSS) and an oscillatory shear stress region distal from the cast (OSS). Both tissue type transglutaminase (TG2) and the plasma transglutaminase Factor XIIIA (FXIIIA) were inhibited by the transglutaminase inhibitor L682.777, delivered by an osmotic minipump (n=8). Results In the OSS region, inhibition of TGs resulted in larger lesions (12673 ± 1327 μm 2 for control versus 24135 ± 3732 μm 2 TG inhibitor, p<0.05), with higher smooth muscle content (10 ± 5% of total plaque area in control versus 38 ± 8% TG inhibitor, p=0.01), lower lipid content (23±5% control versus 5±3% in TG inhibitor, p<0.05) and lower macrophage content (51±10% for control versus 10±3% in TG inhibitor, p<0.05). TG inhibition had no effect on lesion size, lipid accumulation and macrophage infiltration in lesions developed in the LSS region. Conclusion Inhibition of TGs has a profound effect on plaque size and composition in regions of oscillatory shear stress, resulting in larger lesions with a more stable phenotype. Supported by the Netherlands Heart Foundation NHS 2001T038