Prostacyclin agonists reduce early atherosclerosis in hyperlipidemic hamsters. Octimibate and BMY 42393 suppress monocyte chemotaxis, macrophage cholesteryl ester accumulation, scavenger receptor activity, and tumor necrosis factor production.
We determined the effects of two prostacyclin agonists (octimibate and BMY 42393) on the progression of the fatty streak in vivo and on macrophage function in vitro. Hamsters were fed chow plus 0.05% cholesterol and 10% coconut oil. Control hamsters were compared with animals receiving either octimibate (10 or 30 mg/kg per day) or BMY 42393 (30 mg/kg per day). After 10 weeks of treatment, octimibate decreased plasma total cholesterol and triglycerides by 43% and 32%, respectively. Neither agonist affected blood pressure or heart rate. Lesion-prone aortic arches were stained with hematoxylin and oil red O and examined en face. Compared with controls, octimibate and BMY 42393 on average decreased mononuclear cells attached to the luminal surface by 44% and reduced subendothelial macrophage-foam cell number by 56%, foam cell size by 38%, and fatty streak area by 63%. Since octimibate is a putative inhibitor of acyl coenzyme A cholesterol acyltransferase, we studied the effect of both agents on cholesteryl ester metabolism in murine macrophages. At 10 microM, octimibate and BMY 42393 decreased cholesteryl ester accumulation in macrophages by 90% and 41%, respectively. Octimibate inhibited cholesteryl ester synthesis by 96% and increased the rate of cholesteryl ester degradation by 52%. Both prostacyclin agonists reduced macrophage scavenger receptor-mediated uptake of acetylated low density lipoprotein by 24-66% and increased cyclic adenosine monophosphate levels. Octimibate and BMY 42393 inhibited the secretion of tumor necrosis factor by 80-88% when macrophages were activated with lipopolysaccharide. At 10 microM, both agents decreased human monocyte chemotaxis to N-formyl-methionyl-leucyl-phenylalanine by 64-79%. The in vitro results with octimibate and BMY 42393 are consistent with the low number of small foam cells quantified in vivo. We suggest that octimibate and BMY 42393 suppress monocyte-macrophage atherogenic activity and cytokine production and thus inhibit the development of early atherosclerosis.
Kowala
M C
MC
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute (BMS PRI), Princeton, NJ 08543-4000.
Mazzucco
C E
CE
Hartl
K S
KS
Seiler
S M
SM
Warr
G A
GA
Abid
S
S
Grove
R I
RI
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002633:Chemotaxis / Q000187:drug effects; D002788:Cholesterol Esters / Q000378:metabolism; D006224:Cricetinae; D011464:Epoprostenol / Q000502:physiology*; D006949:Hyperlipidemias / Q000150:complications*; D007093:Imidazoles / Q000627:therapeutic use*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D010080:Oxazoles / Q000627:therapeutic use*; D010642:Phenoxyacetates / Q000627:therapeutic use*; D011971:Receptors, Immunologic / Q000378:metabolism; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D002788:Cholesterol Esters; D007093:Imidazoles; D008565:Membrane Proteins; D010080:Oxazoles; D010642:Phenoxyacetates; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha; C080116:BMY 42393; D011464:Epoprostenol; C054659:octimibate