Setanaxib (GKT137831)

GKT137831 attenuates hypoxia-induced H(2)O(2) release, cell proliferation, and TGF-β1 expression and blunted reductions in PPARγ in HPAECs and HPASMCs. ^[2] GKT137831 also prevents oxidative stress in response to hyperglycemia in human aortic endothelial cells. ^[3]

Hypoxic HPASMC and HPAEC proliferation is determined using MTT assay, by Western blotting to detect proliferating cell nuclear antigen (PCNA) expression, or by manual cell counting after Trypan blue staining. Amplex Red Hydrogen Peroxide/Peroxidase Assay Kit is used to measure H2O2 released into the culture media from HPAECs or HPASMCs. After exposure to control or hypoxic environments for 72 hours, Amplex Red reagent is added, and the cells are returned to control or hypoxic environments for an additional hour before fluorescence measurements.

In WT and SOD1mut mice, GKT137831 (60 mg/kg i.g.) blocks liver fibrosis and downregulates markers of oxidative stress, inflammation, and fibrosis. ^[1] GKT137831 (60 mg/kg/d p.o.) also attenuates chronic hypoxia–induced right ventricular hypertrophy, vascular remodeling, lung cell proliferation, and hypoxic alterations in lung PPARγ and TGF-β1 expression in mouse model of chronic hypoxia exposure. ^[2] In diabetic apolipoprotein E-deficient mice, GKT137831 (60 mg/kg/d p.o.) attenuates diabetes mellitus-accelerated atherosclerosis. ^[3] Moreover, in angII-infused c-hNox4Tg mice, GKT137831 abolishes the increase in oxidative stress, suppresses Akt-mTOR and NF-κB signaling pathway and attenuates cardiac remodeling. ^[4]