Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis
Ivana Slámová, Rozita Adib, Stéphan Ellmerich, Michal R. Golos, Janet A. Gilbertson, Nicola Botcher, Diana Canetti, Graham W. Taylor, Nigel B. Rendell, Glenys A. Tennent, Guglielmo Verona, Riccardo Porcari, P. Patrizia Mangione, Julian D. Gillmore, Mark B. Pepys, Vittorio Bellotti, Philip N. Hawkins, Raya Al‐Shawi, J. Paul Simons
Abstract
Abstract Cardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTR S52P . The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α 2 -antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments.