Transglutaminase 2 conformation as a new target to treat vascular dysfunction in aging and diabetes

Abstract

Endothelial dysfunction is an independent risk factor for cardiovascular complications associated with aging and diabetes. Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme with calcium-dependent transamidase activity; it is overactive in aging and diabetes and has been linked with fibrotic processes in the cardiovascular and renal systems (e.g. stiffening, calcification) as well as with endothelial dysfunction in diabetes and inward remodeling in hypertension. These effects have been ascribed to the open TG2 conformation. On the other hand, the closed conformation of TG2 has GTP-binding activity, acting as a G protein in transmembrane signaling, opening potassium channels in vascular smooth muscle cells (VSMCs) and participating in cell survival. This led to the hypothesis that induction of the closed conformation by pharmacological means would present blood-pressure lowering effects and prevent endothelial dysfunction...