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- W4701858 abstract "Angiotensin II (Ang II) increases H 2 O 2 production and vascular smooth muscle cell (VSMCs) hypertrophy, in part through redox-sensitive PI3K/Akt, which is inhibited by catalase overexpression. The relevant molecular mechanism remains unclear. Peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1 α ) is reported to protect from oxidative stress by regulating expression of antioxidant enzymes such as catalase. We thus hypothesized that PGC-1 α may be important mediator for Ang II-induced H2O2 production and vascular hypertrophy. Here we show that Ang II stimulation increases serine phosphorylation of PGC-1 α (2.2 folds) with a peak at 15 min, which is inhibited by LY294002, a specific PI3 kinase inhibitor (98% decrease), and by Akt inhibitor-2/Triciribine (95% decrease). Ang II promotes PGC-1 α phosphorylation mainly at Ser 570 in an Akt-dependent manner. Ang II significantly suppresses Gal4-fused PGC-1 α transcriptional activity in a dose dependent manner, which is partially reversed by PI3K/Akt inhibition. Chromatin immunoprecipitation (ChIP) assay shows that PGC-1 α associates with the catalase promoter and this association is blocked by Ang II in a PI3K/Akt-dependent manner. Consistent with these results, Ang II stimulation time-dependently decreases endogenous catalase expression at both messenger RNA and protein levels. Ang II-induced downregulation of catalase at protein level at 24 hrs is prevented by Akt inhibitor (86%) and by overexpression of PGC-1 α S570A, an Akt phosphorylation site mutant, (75%). Moreover, overexpression of PGC-1 α S570A significantly inhibits Ang II-induced increase in H2O2 production (>80%) and leucine incorporation (>90%) as measured at 12 and 24 hrs, respectively. In summary, Akt-dependent serine phosphorylation of PGC-1 α by Ang II plays an important role for Ang II-induced downregulation of catalase, thereby increasing H2O2 production, which may contribute to ROS-dependent VSMC hypertrophy. These findings provide insight into a novel mechanisms by which Ang II promotes long-term H2O2 production to increase oxidative stress via targeting PGC-1alpha, and mediates metabolic abnormalities." @default.
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- W4701858 date "2008-10-28" @default.
- W4701858 modified "2023-10-18" @default.
- W4701858 title "Abstract 1357: PGC-1 α as a Novel Regulator for Angiotensin II-induced Reactive Oxygen Species Production and Hypertrophy in Vascular Smooth Muscle Cells" @default.
- W4701858 doi "https://doi.org/10.1161/circ.118.suppl_18.s_312-c" @default.
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