Apurinic/apyrimidinic endonuclease 1 inhibits protein kinase C-mediated p66shc phosphorylation and vasoconstriction
Open Access
- 4 April 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 91 (3), 502-509
- https://doi.org/10.1093/cvr/cvr095
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 CβII (PKCβII)-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 PKCβII phosphorylation in mouse endothelial cells. Adenoviral overexpression of APE1 resulted in reduction of oxLDL-induced p66shc and PKCβII phosphorylation. Phorbol 12-myristate 13-acetate (PMA), which stimulates PKCs, induced p66shc phosphorylation and this was inhibited by a selective PKCβII inhibitor. Adenoviral overexpression of PKCβII 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 PKCβII-mediated serine phosphorylation of p66shc, and mitigates vasoconstriction induced by activation of PKC.Keywords
This publication has 43 references indexed in Scilit:
- Reduction of PKCβII activity in smooth muscle cells attenuates acute arterial injuryAtherosclerosis, 2010
- Decreased Superoxide Production in Macrophages of Long-lived p66Shc Knock-out MiceJournal of Biological Chemistry, 2010
- The Many Functions of APE1/Ref-1: Not Only a DNA Repair EnzymeAntioxidants and Redox Signaling, 2009
- Mice deficient in PKC β and apolipoprotein E display decreased atherosclerosisThe FASEB Journal, 2008
- p66ShcDeletion Confers Vascular Protection in Advanced Atherosclerosis in Hypercholesterolemic Apolipoprotein E Knockout MiceEndothelium, 2008
- Genetic deletion of p66 Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stressProceedings of the National Academy of Sciences, 2007
- Apurinic/apyrimidinic endonuclease1/redox factor-1 inhibits monocyte adhesion in endothelial cellsCardiovascular Research, 2006
- Apurinic/Apyrmidinic Endonuclease 1 Regulates Endothelial NO Production and Vascular ToneCirculation Research, 2004
- Redox factor-1: an extra-nuclear role in the regulation of endothelial oxidative stress and apoptosisCell Death & Differentiation, 2002
- Carboxyl-terminal Phosphorylation Regulates the Function and Subcellular Localization of Protein Kinase C βIIPublished by Elsevier ,1999