G protein-coupled receptor Ca2+-linked mitochondrial reactive oxygen species are essential for endothelial/leukocyte adherence

Brian J. Hawkins, Laura A. Solt, Ibrul Chowdhury, Altaf S. Kazi, M. Ruhul Abid, William C. Aird, Michael J. May, J. Kevin Foskett, Muniswamy Madesh

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

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-κB 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-κB 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.

Original languageEnglish (US)
Pages (from-to)7582-7593
Number of pages12
JournalMolecular and cellular biology
Volume27
Issue number21
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Hawkins, B. J., Solt, L. A., Chowdhury, I., Kazi, A. S., Abid, M. R., Aird, W. C., May, M. J., Foskett, J. K., & Madesh, M. (2007). G protein-coupled receptor Ca2+-linked mitochondrial reactive oxygen species are essential for endothelial/leukocyte adherence. Molecular and cellular biology, 27(21), 7582-7593. https://doi.org/10.1128/MCB.00493-07