Eicosanoids and their role in atherosclerosis.
Our laboratory has been actively investigating the role of endogenously synthesized eicosanoids in the control of vascular cholesterol metabolism. Using an in vivo rabbit model, cholesteryl esters (CE) accumulated under the regenerating edge of the endothelium due to reductions in CE hydrolytic activity and the accumulation of LDL. In addition, the aortic neointima immediately formed after de- endothelialization synthesized little PGI2, but regained its capacity to synthesize PGI2 over time of endothelial cell regeneration. Importantly, hypercholesterolemia inhibited the recovery of PGI2-synthetic capacity by the vessel wall using this model. Using cultured arterial smooth muscle cells, PGI2 and its derivatives (but not PGE2 and PGE1) stimulated lysosomal (acid) and cytoplasmic (neutral) CE hydrolase activities and reduced cellular cholesterol content. CE-synthetic activity was unaffected by PGI2 or its stable metabolites, but was inhibited by PGE2. Eicosanoids generated from platelet-neutrophil-smooth muscle cell interactions (including platelet-generated arachidonic acid, 12-HETE, 12,20-diHETE) may be important in the role of eicosanoids in mediating vascular cholesterol metabolism. We also observed that CE-enriched arterial smooth muscle cells have reduced capacity to synthesize PGI2 and PGE2. Collectively, our data suggest that eicosanoids derived from blood-borne cells and the vascular endothelium may regulate cholesterol metabolism in smooth muscle cells, and that eicosanoid regulation of vascular CE content may be impaired during hypercholesterolemia owing to an inability of arterial tissue to generate PGI2 and related eicosanoids.
Hajjar
D P
DP
Department of Biochemistry and Pathology, Cornell University Medical College, New York, NY 10021.
Pomerantz
K B
KB
D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology*; D002784:Cholesterol / Q000378:metabolism; D015777:Eicosanoids / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000378:metabolism; D011464:Epoprostenol / Q000502:physiology*
D015777:Eicosanoids; D002784:Cholesterol; D011464:Epoprostenol