Resumen
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.
Idioma original | English (US) |
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Páginas (desde-hasta) | 7582-7593 |
Número de páginas | 12 |
Publicación | Molecular and cellular biology |
Volumen | 27 |
N.º | 21 |
DOI | |
Estado | Published - nov 2007 |
Publicado de forma externa | Sí |
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology