Transglutaminase 2 Inhibitor LDN 27219 Age-Dependently Lowers Blood Pressure and Improves Endothelium-Dependent Vasodilation in Resistance Arteries.
Transglutaminase 2 (TG2) is an enzyme which in the open conformation exerts transamidase activity, leading to protein cross-linking and fibrosis. In the closed conformation, TG2 participates in transmembrane signaling as a G protein. The unspecific transglutaminase inhibitor cystamine causes vasorelaxation in rat resistance arteries. However, the role of TG2 conformation in vascular function is unknown. We investigated the vascular effects of selective TG2 inhibitors by myography in isolated rat mesenteric and human subcutaneous resistance arteries, patch-clamp studies on vascular smooth muscle cells, and blood pressure measurements in rats and mice. LDN 27219 promoted the closed TG2 conformation and inhibited transamidase activity in mesenteric arteries. In contrast to TG2 inhibitors promoting the open conformation (Z-DON, VA5), LDN 27219 concentration-dependently relaxed rat and resistance human arteries by a mechanism dependent on nitric oxide, large-conductance calcium-activated and voltage-gated potassium channels 7, lowering blood pressure. LDN 27219 also potentiated acetylcholine-induced relaxation by opening potassium channels in the smooth muscle; these effects were abolished by membrane-permeable TG2 inhibitors promoting the open conformation. In isolated arteries from 35- to 40-week-old rats, transamidase activity was increased, and LDN 27219 improved acetylcholine-induced relaxation more than in younger rats. Infusion of LDN 27219 decreased blood pressure more effectively in 35- to 40-week than 12- to 14-week-old anesthetized rats. In summary, pharmacological modulation of TG2 to the closed conformation age-dependently lowers blood pressure and, by opening potassium channels, potentiates endothelium-dependent vasorelaxation. Our findings suggest that promoting the closed conformation of TG2 is a potential strategy to treat age-related vascular dysfunction and lowers blood pressure.
['Pinilla|Estéfano|E|', 'Comerma-Steffensen|Simon|S|', 'Prat-Duran|Judit|J|', 'Rivera|Luis|L|', 'Matchkov|Vladimir V|VV|', 'Buus|Niels Henrik|NH|', 'Simonsen|Ulf|U|']
D000367:Age Factors D000818:Animals D001794:Blood Pressure D004730:Endothelium, Vascular D019204:GTP-Binding Proteins D051036:Large-Conductance Calcium-Activated Potassium Channels D008297:Male D032389:Myocytes, Smooth Muscle D009569:Nitric Oxide D011487:Protein Conformation D000091345:Protein Glutamine gamma Glutamyltransferase 2 D051381:Rats D017208:Rats, Wistar D011503:Transglutaminases D014655:Vascular Resistance D014664:Vasodilation
blood pressure fibrosis nitric oxide potassium channels aging