ICAM-1 cytoplasmic tail regulates endothelial glutathione synthesis through a NOX4/PI3-kinase-dependent pathway.

Free Radical Biology & Medicine
Christopher B PattilloChristopher G Kevil

Abstract

We previously reported that ICAM-1 expression modulates endothelial intracellular glutathione (GSH) metabolism through unknown mechanisms. Here we report that the cytoplasmic tail of ICAM-1 is critically involved in governing intracellular GSH production. Peptides containing the antennapedia cell-permeative sequence (AP) or an AP peptide linked to the transmembrane and cytosolic tail of ICAM-1 (AP-ICAM) were synthesized and used to measure alterations in redox status in cultured endothelial cells and determine their biological effect. Treatment with AP-ICAM significantly increased GSH concentrations and glutamate-cysteine ligase (GCL) activity over time. Measuring reactive oxygen species (ROS) production with DCF revealed a rapid increase in ROS generation after AP-ICAM treatment. Measurement of superoxide production with hydroethidium revealed biphasic production at 30 min and 6h after treatment with AP-ICAM. Apocynin, DPI, catalase, or SOD attenuated AP-ICAM-dependent ROS production, GCL activity, and GSH production, implicating superoxide production and dismutation to peroxide. Consistent with these findings, NOX4 siRNA knockdown blocked AP-ICAM peptide increases in GSH or GCL activity, demonstrating the importance of NADPH ...Continue Reading

Citations

Oct 23, 2013·Pharmacological Reports : PR·Paulina KleniewskaAnna Gorąca
May 29, 2012·Seminars in Cell & Developmental Biology·Shyamal C BirChristopher G Kevil
May 21, 2013·Free Radical Biology & Medicine·Shyamal C BirChristopher B Pattillo
May 28, 2013·American Journal of Physiology. Heart and Circulatory Physiology·Akio MonjiToyoaki Murohara
Jan 13, 2016·British Journal of Pharmacology·F VilhardtG McBean

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