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

作者：Lee Sang Ki; Chung Jae In; Park Myoung Soo; Joo Hee Kyoung; Lee Eun Ji; Cho Eun Jung; Park Jin Bong; Ryoo Sungwoo; Irani Kaikobad; Jeon Byeong Hwa^*

来源：Cardiovascular Research, 2011, 91(3): 502-509.

DOI：10.1093/cvr/cvr095

• p66shc
• Apurinic/apyrimidinic endonuclease1
• Oxidized LDL
• Protein kinase C
• Endothelial cells

Aims 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 beta II (PKC beta II)-mediated p66shc phosphorylation in cultured endothelial cells and PKC-mediated vasoconstriction of arteries.
Methods and results Oxidized low-density lipoprotein (oxLDL) induced p66shc phosphorylation at serine 36 residue and PKC beta II phosphorylation in mouse endothelial cells. Adenoviral overexpression of APE1 resulted in reduction of oxLDL-induced p66shc and PKC beta II phosphorylation. Phorbol 12-myristate 13-acetate (PMA), which stimulates PKCs, induced p66shc phosphorylation and this was inhibited by a selective PKC beta II inhibitor. Adenoviral overexpression of PKC beta 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.
Conclusion APE1 suppresses oxLDL-induced p66shc activation in endothelial cells by inhibiting PKC beta II-mediated serine phosphorylation of p66shc, and mitigates vasoconstriction induced by activation of PKC.

• 出版日期2011-8-1
• 单位河北医科大学