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Mol. Cell. Biol. doi:10.1128/MCB.00493-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

GPCR Ca²⁺-linked Mitochondrial Reactive Oxygen Species are Essential for Endothelial/Leukocyte Adherence

Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.; Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA; Deparment of Cancer Biology, University of Pennsylvania, Philadelphia PA 19104, USA

^* To whom correspondence should be addressed. Email: madeshm{at}mail.med.upenn.edu.

	Abstract

Receptor-mediated signaling is commonly associated with multiple functions including the production of reactive oxygen species (ROS). However, whether mitochondrial-derived superoxide (mROS) contributes directly to physiological signaling is controversial. Here we demonstrate a previously unknown mechanism in which physiologic Ca²⁺-evoked mROS production plays a pivotal role in endothelial cell (EC) activation and leukocyte firm adhesion. G-protein coupled receptor (GPCR) and tyrosine kinase-mediated inositol 1,4,5-trisphosphate-dependent mitochondrial Ca²⁺ uptake resulted in NADPH oxidase-independent mROS production. However, GPCR-linked mROS production did not alter mitochondrial function or trigger cell death, but rather contributed to activation of NF-B and leukocyte adhesion via the EC induction of ICAM-1. Dismutation of mROS by MnSOD overexpression and a cell-permeable superoxide dismutase mimetic ablated NF-B transctiptional activity and facilitated leukocyte detachment from the endothelium under simulated circulation following GPCR- but not cytokine-induced activation. These results demonstrate that mROS is the downstream effector molecule that translates receptor-mediated Ca²⁺ signals into pro-inflammatory signaling and leukocyte/EC firm adhesion.