Roles of platelet and endothelial cell COX-1 in hypercholesterolemia-induced microvascular dysfunction.
Aspirin is a common preventative therapy in patients at risk for cardiovascular diseases, yet little is known about how aspirin protects the vasculature in hypercholesterolemia. The present study determines whether aspirin, nitric oxide-releasing aspirin (NCX-4016), a selective cyclooxygenase (COX)-1 inhibitor (SC560), or genetic deficiency of COX-1 prevents the inflammatory and prothrombogenic phenotype assumed by hypercholesterolemic (HC) venules. Aspirin or NCX-4016 (60 mg/kg) was administered orally for the last week of a 2-wk HC diet. COX-1-deficient (COX-1(-/-)) and wild-type (WT) mice were transplanted with WT (WT/COX-1(-/-)) or COX-1(-/-) (COX-1(-/-)/WT) bone marrow, respectively. HC-induced adhesion of platelets and leukocytes in murine intestinal venules, observed with intravital fluorescence microscopy, was greatly attenuated in aspirin-treated mice. Adhesion of aspirin-treated platelets in HC venules was comparable to untreated platelets, whereas adhesion of SC560-treated platelets was significantly attenuated. HC-induced leukocyte and platelet adhesion in COX-1(-/-)/WT chimeras was comparable to that in SC560-treated mice, whereas the largest reductions in blood cell adhesion were in WT/COX-1(-/-) chimeras. NCX-4016 treatment of platelet recipients or donors attenuated leukocyte and platelet adhesion independent of platelet COX-1 inhibition. Platelet- and endothelial cell-associated COX-1 promote microvascular inflammation and thrombogenesis during hypercholesterolemia, yet nitric oxide-releasing aspirin directly inhibits platelets independent of COX-1.
Tailor
Anitaben
A
Department of Molecular and Cellular Physiology, Health Sciences Center, Louisiana State University, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.
Wood
Katherine C
KC
Wallace
John L
JL
Specian
Robert D
RD
Granger
D Neil
DN
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D016026:Bone Marrow Transplantation; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects; D002678:Chimera / Q000378:metabolism; D002791:Cholesterol, Dietary; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D020030:Nitric Oxide Donors / Q000494:pharmacology* / Q000627:therapeutic use; D010973:Platelet Adhesiveness / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014699:Venules / Q000187:drug effects / Q000201:enzymology
D002791:Cholesterol, Dietary; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D011720:Pyrazoles; C115461:SC 560; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; C102148:nitroaspirin; D001241:Aspirin