Cholesterol efflux is defective in macrophages from atherosclerosis-susceptible White Carneau pigeons relative to resistant show racer pigeons.

Abstract

White Carneau (WC) pigeons are susceptible to the development of aortic atherosclerosis, whereas Show Racer (SR) pigeons are resistant, even though there are no differences in the known risk factors, including plasma cholesterol levels, lipoproteins, blood pressure, etc. Although this suggests that the difference in atherosclerosis susceptibility between WC and SR pigeons may be mediated at the level of the arterial wall, we have yet to identify a mechanism that can account for this difference. In pigeons as in other species (including humans), macrophages play a major role in the pathogenesis of atherosclerosis. Pigeon macrophages have multiple mechanisms for the uptake of lipoproteins and the accumulation of cholesteryl esters. To date, however, no differences in lipoprotein uptake between macrophages of WC and SR pigeons have been identified that could explain the difference in atherosclerosis susceptibility. In the present study we explored the alternative hypothesis that there are differences in the rate of cholesteryl ester clearance from peritoneal macrophages isolated from the two breeds of pigeons. Cholesterol efflux studies were conducted with elicited pigeon peritoneal macrophages that were loaded with cholesteryl ester either in vitro by incubation with rabbit beta-very low density lipoprotein or in vivo by isolation of macrophages from birds fed a cholesterol-containing diet. Using these techniques we were able to load WC and SR macrophages consistently with cholesteryl esters to levels typical of arterial foam cells (150-1,150 micrograms/mg cell protein). Under these cholesterol loading conditions there was no net efflux of cholesterol from either WC or SR macrophages when incubated for up to 24 hours in the presence of pigeon or human high density lipoprotein (HDL), fetal bovine serum, or lipoprotein-deficient serum. Under the same conditions, efflux of cholesterol from mouse peritoneal macrophages was stimulated by human and pigeon HDL. Despite the inability of HDL, lipoprotein-deficient serum, or fetal bovine serum to promote net cholesterol efflux, apoprotein (apo) HDL/phosphatidylcholine (PC) vesicles stimulated cholesteryl ester clearance from both WC and SR pigeon macrophages but at a significantly slower rate from WC pigeon macrophages. When incubated in the presence of excess apoHDL/PC (400 micrograms/ml), the rate of depletion of cellular cholesteryl esters was log-linear for at least 48 hours. WC macrophages cleared an average of only 9% of their cholesteryl esters in 24 hours when incubated with excess apoHDL/PC, whereas SR macrophages reduced their cholesteryl ester content by an average of 42%.(ABSTRACT TRUNCATED AT 400 WORDS)