Transglutaminase 2 Conformation as a New Target to Treat Vascular Dysfunction in Aging and Diabetes

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, leída el 16/09/2020. Tesis formato europeo (compendio de artículos) ; 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. ; Endothelcelle dysfunktion er en selvstændig risikofaktor for kardiovaskulære komplikationer vedaldring og diabetes. Transglutaminase 2 (TG2) er et udbredt enzym med calcium-afhængigttransamidase aktivitet. Enzymet er over-aktiv hos ældre personer samt personer med diabetes, oger set i sammenhæng med fibrotiske processer i det kardiovaskulære system og nyrerne (f.eks. øgetstivhed og forkalkning) såvel som ved endothelcelle dysfunktion ved diabetes og forhøjet blodtryk.Disse effekter er blevet tillagt den åbne konformation af TG2. Den lukkede protein konformationaf TG2 har GTP-bindende aktivitet og fungerer som G-protein i transmembran-signalering,hvorved der åbnes kaliumkanaler i vaskulære glatte muskelceller (SMCs), og TG2 bevirker ogsåøget celleoverlevelse. Dette har ledt til hypotesen, at induktion af den lukkede konformation vha.farmakologiske metoder vil resultere i blodtryksnedsættende effekter og forebygge ...