8-isoprostane increases scavenger receptor A and matrix metalloproteinase activity in THP-1 macrophages, resulting in long-lived foam cells.
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 F(2)-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.


RESULTS
8-isoprostane (10 micro M) augmented the oxLDL-induced (20 micro g 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.
Scholz
H
H
Rikshospitalet University Hospital, University of Oslo, Norway.
Aukrust
P
P
Damås
J K
JK
Tonstad
S
S
Sagen
E L
EL
Kolset
S O
SO
Hall
C
C
Yndestad
A
A
Halvorsen
B
B
D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism*; D051116:Receptors, Scavenger; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D020169:Caspases; D020780:Matrix Metalloproteinase 9