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1 CIHR Group in Matrix Dynamics, University of Toronto, Faculty of Dentistry, Toronto, Ontario, Canada; Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
2 Faculty of Medicine, University of Toronto, Toronto, Ontario, Cambodia
* To whom correspondence should be addressed. E-mail: ron.zohar{at}utoronto.ca.
Reperfusion-induced oxidative injury to the myocardium promotes activation and proliferation of cardiac fibroblasts and repair by scar formation. Osteopontin (OPN) is a pro-inflammatory cytokine that is up-regulated after reperfusion. To determine if OPN enhances fibroblast survival after exposure to oxidants, cardiac fibroblasts from wild-type (WT) or OPN-/- mice were treated in vitro with H2O2 to model reperfusion injury. Within 1 hour, membrane permeability to propidium iodide (PI) was increased from 5% to 60% in OPN-/- cells but was increased to only 20% in WT cells. In contrast, after 1-8 hours of treatment with H2O2, the % of TUNEL-stained cells was >2-fold higher in WT than OPN-/- cells. Electron microscopy of WT cells treated with H2O2 showed chromatin condensation, nuclear fragmentation, and cytoplasmic and nuclear shrinkage, consistent with apoptosis. In contrast, H2O2-treated OPN-/- cardiac fibroblasts exhibited cell and nuclear swelling, and membrane disruption, indicative of cell necrosis. Treatment of OPN-/- and WT cells with a cell-permeable caspase 3 inhibitor reduced % TUNEL staining by >4-fold in WT cells but decreased staining in OPN-/- cells by ~30%. While the % PI-permeable WT cells was reduced 3-fold, the %-PI permeable OPN-/- cells was not altered. Restoration of OPN expression in OPN-/- fibroblasts reduced % PI-permeable cells but not TUNEL staining after H2O2 treatment. Thus H2O2-induced cell death in osteopontin-deficient cardiac fibroblasts is mediated by a caspase 3-independent, necrotic pathway. We suggest that the increased expression of OPN in the myocardium after reperfusion may promote fibrosis by protecting cardiac fibroblasts from cell death.
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