8‐isoprostane increases scavenger receptor A and matrix metalloproteinase activity in THP‐1 macrophages, resulting in long‐lived foam cells

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Abstract
Background Oxidative stress is a key factor in atherogenesis, in which it is closely associated with the inflammation and formation of bioactive lipids. Although 8‐isoprostane is regarded as a reliable marker of oxidative stress in vivo, the pathogenic role of this F2‐isoprostane in atherogenesis is far from clear. Based on the important role of foam cells in the initiation and progression of atherosclerosis we hereby examined the ability of 8‐isoprostane to modulate oxidized (ox)LDL‐induced foam cell formation and the function of these cells, particularly focusing on the effect on matrix degradation. Methods and results 8‐isoprostane (10 µM) augmented the oxLDL‐induced (20 µg mL−1) lipid accumulation of THP‐1 macrophages evaluated by Oil‐Red‐O staining and lipid mass quantification (colourimetric assay). Additionally, 8‐isoprostane induced the expression of the scavenger receptor A type 1 (MSR‐1) [mRNA and protein level], assessed by RT‐PCR and Western blotting, respectively. Moreover, 8‐isoprostane counteracted the oxLDL‐induced apoptosis of these cells, involving both mitochondrial‐protective and caspase‐suppressive mechanisms. Along with these changes, 8‐isoprostane increased the oxLDL‐induced gene expression of matrix metalloproteinase (MMP)‐9 and its endogenous inhibitor [i.e. tissue inhibitor of MMP (TIMP)‐1] accompanied by enhanced total MMP activity. Conclusions We show that 8‐isoprostane increases foam cell formation at least partly by enhancing MSR‐1 expression and by inhibiting apoptosis of these cells, inducing long‐lived foam cells with enhanced matrix degrading capacity. Our findings further support a role for 8‐isoprostane not only as a marker of oxidative stress in patients with atherosclerotic disorders, but also as a mediator in atherogenesis and plaque destabilization.