title: Elevated transglutaminase 2 activity is associated with hypoxia-induced experimental pulmonary hypertension in mice.
abstract: Previous studies in human patients and animal models have suggested that transglutaminase 2 (TG2) is upregulated in pulmonary hypertension (PH), a phenomenon that appears to be associated with the effects of serotonin (5-hydroxytryptamine; 5-HT) in this disease. Using chemical tools to interrogate and inhibit TG2 activity in vivo, we have shown that pulmonary TG2 undergoes marked post-translational activation in a mouse model of hypoxia-induced PH. We have also identified irreversible fluorinated TG2 inhibitors that may find use as non-invasive positron emission tomography probes for diagnosis and management of this debilitating, lifelong disorder. Pharmacological inhibition of TG2 attenuated the elevated right ventricular pressure but had no effect on hypertrophy of the right ventricle of the heart. A longitudinal study of pulmonary TG2 activity in PH patients is warranted.
authors.affiliation: Departments of †Chemical Engineering and ‡Chemistry, Stanford University , Stanford California 94305, United States.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: DiRaimondo
authors.forename: Cornelius
authors.initials: C
authors.lastname: Klöck
authors.forename: Rod
authors.initials: R
authors.lastname: Warburton
authors.forename: Zachary
authors.initials: Z
authors.lastname: Herrera
authors.forename: Krishna
authors.initials: K
authors.lastname: Penumatsa
authors.forename: Deniz
authors.initials: D
authors.lastname: Toksoz
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hill
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
authors.forename: Barry
authors.initials: B
authors.lastname: Fanburg
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D000860:Hypoxia / Q000150:complications* / Q000201:enzymology* / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins