Cholesterol metabolism is altered by hydrolytic metabolites of prostacyclin in arterial smooth muscle cells.
Cholesteryl esters are the major lipids that accumulate in arteries during atherogenesis. The mechanisms responsible for this lipid accretion have not been completely defined. Our previous experiments have shown that prostacyclin (PGI2) enhances cholesteryl ester catabolism by increasing cyclic AMP in cultured arterial smooth muscle cells. However, PGI2 is rapidly degraded under physiologic conditions and endogenous levels of PGI2 in the human circulation are extremely low. These findings suggest that it is not a circulating hormone. We tested the hypothesis that stable PGI2 metabolites alter cholesteryl ester metabolism and cellular lipid accumulation. Ten to 100 nM dinor-6-keto PGF1 alpha, 13,14-dihydro-6,15-diketo PGF1 alpha, and 6,15-diketo PGF1 alpha increased cyclic AMP levels significantly two- to threefold with a concomitant enhancement of both lysosomal and cytoplasmic cholesteryl ester hydrolytic activities. Cholesteryl ester synthesis was unchanged by the PGI2 metabolites. When cyclic AMP concentrations were maintained at basal levels by an adenylate cyclase inhibitor, no effect on cholesteryl ester hydrolysis was observed following addition of PGI2 metabolites to the cells. Furthermore, addition of PGI2 metabolites during a 1-week culture period reduced free and esterified cholesterol by 50%. These data suggest that PGI2 metabolites: 1) decrease intracellular cholesterol accumulation by increasing cholesteryl ester catabolism; 2) act via enhancement of cyclic AMP; and, 3) may represent circulating regulators of arterial cholesteryl ester metabolism.
D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D011464:Epoprostenol / Q000502:physiology; D066298:In Vitro Techniques; D008247:Lysosomes / Q000201:enzymology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D002787:Sterol Esterase / Q000378:metabolism
D002788:Cholesterol Esters; D015121:6-Ketoprostaglandin F1 alpha; C033371:6,15-diketo-13,14-dihydroprostaglandin F1alpha; D002784:Cholesterol; D011464:Epoprostenol; D000242:Cyclic AMP; D002787:Sterol Esterase