Apurinic/apyrimidinic endonuclease 1 inhibits protein kinase C-mediated p66shc phosphorylation and vasoconstriction.

ABSTRACT: Phosphorylation of the adaptor protein p66shc is essential for p66shc-mediated oxidative stress. We investigated the role of the reducing protein/DNA repair enzyme apurinic/apyrimidinic endonuclease1 (APE1) in modulating protein kinase C?II (PKC?II)-mediated p66shc phosphorylation in cultured endothelial cells and PKC-mediated vasoconstriction of arteries.Oxidized low-density lipoprotein (oxLDL)induced p66shc phosphorylation at serine 36 residue and PKC?II phosphorylation in mouse endothelial cells. Adenoviral overexpression of APE1 resulted in reduction of oxLDL-induced p66shc and PKC?II phosphorylation. Phorbol 12-myristate 13-acetate (PMA), which stimulates PKCs, induced p66shc phosphorylation and this was inhibited by a selective PKC?II inhibitor. Adenoviral overexpression of PKC?II also increased p66shc phosphorylation. Overexpression of APE1 suppressed PMA-induced p66shc phosphorylation. Moreover, PMA-induced p66shc phosphorylation was augmented in cells in which APE1 was knocked down. PMA increased cytoplasmic APE1 expression, compared with the basal condition, suggesting the role of cytoplasmic APE1 against p66shc phosphorylation. Finally, vasoconstriction induced by phorbol-12,13, dibutylrate, another PKC agonist, was partially inhibited by transduction of Tat-APE1 into arteries.APE1 suppresses oxLDL-induced p66shc activation in endothelial cells by inhibiting PKC?II-mediated serine phosphorylation of p66shc, and mitigates vasoconstriction induced by activation of PKC.

SUBMITTER: Lee SK 

PROVIDER: S-EPMC3139447 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature