Lipid peroxidation and platelet activation in murine atherosclerosis.
BACKGROUND
Lipid peroxidation and platelet activation are thought to be important contributors to the pathogenesis of atherosclerosis. The relevance of their interaction in vivo, however, is unknown.


RESULTS
LDL receptor-deficient (LDLR(-/-)) mice on a high-fat diet developed extensive atherosclerosis and had increased urinary levels of 8,12-iso-isoprostane (iP) F(2alpha)-VI and 2,3-dinor-thromboxane (Tx) B(2), markers of in vivo lipid peroxidation and platelet activation, respectively. Vitamin E supplementation suppressed 8,12-iso-iPF(2alpha)-VI biosynthesis and reduced atherosclerosis (65%) without having a significant effect on lipid levels or TxB(2) biosynthesis. Addition of the platelet inhibitor indomethacin to vitamin E simultaneously suppressed 8,12-iso-iPF(2alpha)-VI and TxB(2), significantly reduced soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1, and remarkably, further reduced atherosclerosis (80%).


CONCLUSIONS
These results indicate that in vivo lipid peroxidation and platelet activation coexist in murine atherosclerosis and that lipid peroxidation does not contribute to platelet activation and reflects the oxidant component of the inflammatory response. Our findings suggest that oxidant stress and platelet activation represent 2 distinct therapeutic targets in atherogenesis. We propose that a combination of antioxidants and platelet inhibitors might be rationally evaluated in the prevention of progression of human atherosclerosis.
Cyrus
T
T
Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania, Philadelphia, USA.
Tang
L X
LX
Rokach
J
J
FitzGerald
G A
GA
Praticò
D
D
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004036:Diet, Atherogenic; D019587:Dietary Supplements; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000652:urine; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007150:Immunohistochemistry; D007213:Indomethacin / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013928:Thromboxane A2 / Q000652:urine; D013929:Thromboxane B2 / Q000097:blood; D014810:Vitamin E / Q000494:pharmacology*
C115626:8,12-iso-isoprostane F2alpha-VI; D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D008055:Lipids; D011973:Receptors, LDL; D014810:Vitamin E; D013929:Thromboxane B2; D013928:Thromboxane A2; D015237:Dinoprost; D007213:Indomethacin