Lipid peroxidation and platelet activation in murine atherosclerosis

Background-Lipid peroxidation and platelet activation are thought to be imp ortant contributors to the pathogenesis of atherosclerosis. The relevance o f their interaction in vivo, however, is unknown. Methods and Results-LDL receptor- deficient (LDLR-/-) mice on a high-fat di et developed extensive atherosclerosis and had increased urinary levels of 8,12-iso-isoprostane (iP) F-2 alpha-VI and 2,3-dinor-throt-nboxane (Tx) B-2 , markers of in vivo lipid peroxidation and platelet activation, respective ly. Vitamin E supplementation suppressed 8,12-iso-iPF(2 alpha)-VI biosynthe sis and reduced atherosclerosis (65%) without having a significant effect o n lipid levels or TxB(2) biosynthesis. Addition of the platelet inhibitor i ndomethacin to vitamin E simultaneously suppressed 8,12-iso-iPF(2 alpha)-VI and TxB(2), significantly reduced soluble intercellular adhesion molecule- 1 and monocyte chemoattractant protein-1, and remarkably, further reduced a therosclerosis (80%). Conclusions-These results indicate that in vivo lipid peroxidation and plat elet activation coexist in murine atherosclerosis and that lipid peroxidati on does not contribute to platelet activation and reflects the oxidant comp onent of the inflammatory response. Our findings suggest that oxidant stres s and platelet activation represent 2 distinct therapeutic targets in ather ogenesis. We propose that a combination of antioxidants and platelet inhibi tors might be rationally evaluated in the prevention of progression of huma n atherosclerosis.