An apolipoprotein A-I mimetic works best in the presence of apolipoprotein A-I.

Ou et al 1 report that an apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, reduced wall thickness and improved vasoreactivity in the fascialis artery (internal diameter 180 to 240 m) in low-density lipoprotein (LDL) receptor–null mice on a Western diet. If the mice also lacked apoA-I, D-4F improved vasoreactivity but it did not reduce wall thickness. The authors concluded that apoA-I or some critical threshold of high-density lipoprotein (HDL)-cholesterol was required for maximum effectiveness of D-4F.1 In previous studies these authors reported that LDL caused endothelial nitric oxide synthase to produce more superoxide anion relative to nitric oxide and the balance between nitric oxide and superoxide anion was restored by the apoA-I mimetic peptide 4F.2 In vivo 4F improved vasoreactivity in LDL receptor null mice fed a Western diet and in a mouse model of sickle cell disease.3 Both of these mouse models were wild-type for apoA-I.3 4F is an 18-aa peptide that has no sequence homology with apoA-I but forms a class A amphipathic helix and mimics the lipid binding properties of apoA-I.4 Oral administration of 4F synthesized from all D-amino acids (D-4F) has been shown to dramatically reduce atherosclerosis in mouse models with wildtype apoA-I.5 Oral D-4F synergized with pravastatin to increase intestinal apoA-I synthesis and increase plasma apoA-I levels and caused lesion regression in old apoE-null mice.6 Oral administration of D-4F to apoE-null or C57BL/6 mice caused the formation of small cholesterol-containing particles with premobility that were enriched in apoA-I and paraoxonase activity, rendered HDL antiinflammatory, and promoted reverse cholesterol transport from intraperitoneally injected cholesterol-loaded macrophages.7 Oral D-4F also significantly reduced lipoprotein lipid hydroperoxides (LOOH) except for preHDL fractions in which apoA-I, paraoxonase activity, and LOOH all increased.7 Oral administration of D-4F to monkeys with wild-type apoA-I decreased lipoprotein-LOOH,8 increased paraoxonase activity,4 caused the formation of preHDL,4 and rendered HDL antiinflammatory.8 Addition of D-4F to human plasma in vitro at a concentration of 250 ng/mL reduced HDL-LOOH, increased paraoxonase activity, increased apoA-I in preHDL and rendered HDL antiinflammatory.4 The inflammatory properties of HDL appear to be inversely correlated with the ability of HDL to promote cholesterol efflux from macrophages (ie, antiinflammatory HDL is better able to promote cholesterol efflux).9 Ou et al1 reported that treatment with D-4F reduced the association of myeloperoxidase (MPO) with apoA-I in vivo (but not in vitro) and decreased 3-nitrotyrosine content of apoA-I without altering plasma MPO levels. Nitric oxide–derived oxidants (as measured by nitrotyrosine levels) were significantly higher in patients with coronary heart disease (CHD) than in patients without CHD, and statin therapy significantly reduced nitrotyrosine levels, with a magnitude similar to the reductions in total cholesterol and LDL particle number but independent of alterations in C-reactive protein (CRP).10 ApoA-I in human atheroma and in human serum is a selective target for MPO-catalyzed nitration and chlorination.11 As a result of these oxidative alterations of apoA-I there was a marked decrease in the ability of the modified apoA-I to promote cholesterol efflux from macrophages via the ATP binding cassette (ABC) A1 pathway.11 Specific tyrosine residues in apoA-I were altered by MPOmediated nitration and chlorination and resulted in decreased lipid binding and a decrease in ABCA1-dependent cholesterol efflux from macrophages.12 However, recombinant apoA-I without tyrosine residues was equally susceptible to dose-dependent MPO-mediated loss of ABCA1-dependent cholesterol acceptor activity and loss of lipid binding activity, indicating that nitroand chlorotyrosine residues were a marker of MPO modification of apoA-I but were not responsible for the loss of function.13 Tyrosine modification in human atherosclerotic intima was 6-fold higher than in circulating HDL and MPO epitopes colocalized with nitrotyrosine.14 HDL from CHD patients contained twice as much 3-nitrotyrosine as did HDL from healthy subjects.14 MPO was identified as a component of lesion HDL, suggesting that MPO and HDL directly interact in atherosclerotic lesions.15 Because D-4F treatment restored vasodilation in both the presence and absence of apoA-I but failed to render HDL antiinflammatory and failed to reduce the thickness of the fascialis artery in the absence of apoA-I, it was concluded that either the presence of apoA-I or some critical level of HDL-cholesterol was required for D-4F to reduce vessel wall thickness.1 The work of Moore et al16 indicates that apoA-I inhibits atherosclerosis by promoting macrophage reverse cholesterol transport and HDL antiinflammatory function independent of HDL-cholesterol levels, and thus suggests that the absence of apoA-I was responsible for the findings of Ou et al with regard The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the David Geffen School of Medicine (M.N., A.M.F.) at the University of California, Los Angeles; and the Department of Medicine (G.M.A.), Atherosclerosis Research Unit, University of Alabama, Birmingham. M.N., G.M.A., and A.M.F. are principals in Bruin Pharma. Correspondence to Mohamad Navab, PhD, Room 47-123 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1679. E-mail mnavab@mednet. ucla.edu (Circ Res. 2005;97:1085-1086.) © 2005 American Heart Association, Inc.