Roles of platelet and endothelial cell COX-1 in hypercholesterolemia-induced microvascular dysfunction.

Abstract

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.

• Authors: Anitaben Tailor, Katherine C Wood, John L Wallace, Robert D Specian, D Neil Granger
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 293 Issue 6 Pg. H3636-42 (Dec 2007) ISSN: 0363-6135 [Print] United States
• PMID: 17933963 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cholesterol, Dietary
• Cyclooxygenase Inhibitors
• Membrane Proteins
• Nitric Oxide Donors
• Pyrazoles
• SC 560
• Cyclooxygenase 1
• Ptgs1 protein, mouse
• nitroaspirin
• Aspirin

Topics

• Animals
• Aspirin (analogs & derivatives, pharmacology, therapeutic use)
• Blood Platelets (drug effects, enzymology)
• Bone Marrow Transplantation
• Cardiovascular Diseases (enzymology, etiology, physiopathology, prevention & control)
• Cell Adhesion (drug effects)
• Chimera (metabolism)
• Cholesterol, Dietary
• Cyclooxygenase 1 (deficiency, genetics, metabolism)
• Cyclooxygenase Inhibitors (pharmacology, therapeutic use)
• Disease Models, Animal
• Endothelial Cells (drug effects, enzymology)
• Endothelium, Vascular (drug effects, enzymology, physiopathology)
• Hypercholesterolemia (chemically induced, complications, drug therapy, enzymology, physiopathology)
• Leukocytes (drug effects)
• Male
• Membrane Proteins (deficiency, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Fluorescence
• Microscopy, Video
• Nitric Oxide Donors (pharmacology, therapeutic use)
• Platelet Adhesiveness (drug effects)
• Pyrazoles (pharmacology, therapeutic use)
• Venules (drug effects, enzymology)