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G Protein-Coupled Receptor Ca²⁺-Linked Mitochondrial Reactive Oxygen Species Are Essential for Endothelial/Leukocyte Adherence ^,

Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,¹ Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,² Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts,³ Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104,⁴ Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104⁵

Received 21 March 2007/ Returned for modification 20 June 2007/ Accepted 16 August 2007

Receptor-mediated signaling is commonly associated with multiple functions, including the production of reactive oxygen species. However, whether mitochondrion-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 intercellular adhesion molecule 1. Dismutation of mROS by manganese superoxide dismutase overexpression and a cell-permeative superoxide dismutase mimetic ablated NF-B transcriptional 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 proinflammatory signaling and leukocyte/EC firm adhesion.

Published ahead of print on 27 August 2007.

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