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HDL and their main apolipoprotein (apo) constituent apoA-I are antiatherogenic. This has been predominantly attributed to the ability of apoA-I/HDL to efflux cholesterol from macrophages within atherosclerotic plaques. It is now emerging that a number of the protective properties of HDL may be due to their effects on the endothelium.In addition to their well characterized anti-inflammatory and antioxidant effects, apoA-I and HDL regulate several other key biological pathways known to preserve endothelial function and promote vascular repair. The ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, and the scavenger receptor B type 1 mediate multiple intracellular signaling pathways as well as the efflux of cholesterol and/or oxysterols in response to apoA-I/HDL. Although cholesterol efflux triggers a host of signaling events in endothelial cells, there is evidence that some of the beneficial actions of HDL may occur independently of efflux.Current data suggest that in endothelial cells ABCA1 and ABCG1 mediate the activation of intracellular signaling pathways primarily through the efflux of cholesterol and oxysterols to apoA-I/HDL. Interaction between HDL and scavenger receptor B type 1 initiates the greatest number of known signaling pathways and there is evidence that some of these are activated independent of efflux.