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Integrative Physiology |
From the Departments of Surgery, Division of Pediatric Surgery (J.O., J.W., H.X., Z.O., D.W.J., P.S., J.C.D., S.K., K.T.O., K.A.P.), Childrens Research Institute (J.O., J.W., H.X., Z.O., P.S., J.C.D., K.T.O., K.A.P.), and Cardiovascular Center (J.O., J.W., H.X., Z.O., K.T.O., K.A.P.), Medical College of Wisconsin, Milwaukee; Guangzhou Institute of Respiratory Disease, Division of Cardiothoracic Surgery (J.O.), and Department of Medicine, Division of Cardiology (Z.O.), The First Affiliated Hospital of Guangzhou Medical College, China; Department of Pathology (M.G.S.-T.), Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to Kirkwood A. Pritchard, Jr, PhD, Medical College of Wisconsin, Pediatric Surgery, CRI, CVC, M-4060, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail kpritch{at}mcw.edu
| Abstract |
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Key Words: cardiovascular diseases hypercholesterolemia lipoproteins nitric oxide synthase vasodilation
| Introduction |
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We previously reported L-4F, when administered by IP injection, increased eNOS-dependent vasodilation of small arteries from hypercholesterolemic Ldlr/ mice and from transgenic sickle cell mice.6 D-4F is the same as L-4F, except it is synthesized from D-amino acids. In the D conformation, 4F is resistant to metabolism compared with 4F synthesized from L-amino acids, which is rapidly degraded after oral administration.8 Oral D-4F reduced lesions in Ldlr/ mice fed WD by more than 79% by restoring HDL function without significantly altering cholesterol or HDL cholesterol levels.7 Interestingly, D-4F also reduced lesions in apoE/ mice, which were hypercholesterolemic from birth.7 However, to date, no studies have been performed to determine whether oral D-4F also restores vasodilation in hypercholesterolemic mice.
D-4F is believed to protect vascular function by binding proinflammatory lipids.8 Proinflammatory oxysterols, such as hydroxycholesterol increase apoptosis of endothelial cells,9,10 whereas other proinflammatory lipids have been shown to increase susceptibility of HDL to oxidation.11 Previous studies by Reddy et al12 revealed 22(R)-hydroxycholesterol (22-OHC), 1 of several forms of oxysterols found in atherosclerotic lesions,13 increases ATP-binding cassette transporter-1 (ABCA-1) expression. Endothelial cells typically maintain an antioxidant phenotype until exposed to LDL containing a critical threshold of lipid peroxides, at which point they are converted into a prooxidant phenotype that promotes LDL oxidation.14 Likewise, when endothelial cells are exposed to 22-OHC, they become proinflammatory and promote oxidation of LDL via ABCA-1 transportation of oxidized phospholipids from the endothelial cell to the LDL particle.12 As 22-OHC does not contain a hydroperoxide for initiating or propagating oxidation, the mechanism by which 22-OHCtreated endothelial cells take on a proinflammatory phenotype is likely attributable to altered cell signaling more than lipid peroxidation.
Recently, it was reported myeloperoxidase (MPO) binds to HDL and subsequently increases nitration of apoA-I, which correlates with a decrease in the ability of HDL to promote cholesterol efflux from cholesterol-loaded macrophages.15 Although the role of MPO in atherosclerosis in mice is controversial,16,17 in murine studies where neutrophils are clearly involved, MPO has been implicated as a mechanism of lipid peroxidation and vascular endothelial cell dysfunction18 in ways that are consistent with how MPO is believed to promote atherosclerosis in humans.19,20
The objectives here were to determine (1) mechanisms by which D-4F improves vasodilation in murine models of hypercholesterolemia; (2) whether increases in vasodilation correlate with changes in vessel wall architecture; (3) mechanisms by which D-4F protects HDL against oxidative stress; and (4) mechanisms by which D-4F reduces vessel wall thickness. Our findings indicate D-4F improves vasodilation in hypercholesterolemic Ldlr/ mice by increasing eNOS function but reduces vessel wall thickness in hypercholesterolemic Ldlr/ mice by an HDL-dependent mechanism.
| Materials and Methods |
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D-4F and L-4F
D-4F and L-4F (Ac-DWFKAFYDKVAEKFKEAFNH2) were synthesized as described.6,7
Vasodilation
Vasodilation of pressurized facialis arteries (180 to 280 µm) was determined as before.6
Wall Thickness
At the end of incubation with papaverine (104 mol/L, 4 minutes),6 an index of wall thickness was calculated using the following formula: ([outside diameterinside diameter]/2)/outside diameter.
Plasma Cholesterol, HDL Cholesterol, and Proinflammatory HDL
Plasma cholesterol and HDL cholesterol were determined by cholesterol oxidase/esterase assays using Cholesterol E and HDL Cholesterol E kits, respectively, from Wako Chemicals USA Inc (Richmond, Va). After quantification of HDL, proinflammatory HDL was determined.
The proinflammatory HDL assay is based on the observation that relative rates of dichlorofluorescein (DCF) fluorescence are proportional to the levels of seeding molecules of lipid hydroperoxides in HDL.11 Briefly, 1 µg of HDL cholesterol was incubated with CuCl2 (5 µmol/L, final concentration) for 1 hour using a 384-well microtiter plate from MJ Research Inc (Waltham, Mass). After incubation, 1 µL of DCF solution (2 mg/mL) was added to the HDL-Cu2+ mixture in a total volume of 30 µL. Rates of fluorescence (excitation, 485 nm; emission, 530 nm) were determined on a LJL Biosystem Analyst HT from Molecular Devices Corp (Sunnyvale, Calif) over the next 2 hours at 30-minute intervals.
Effects of 22-OHC on Vascular Endothelial Cell ·NO and O2· Balance and Expression of ABCA-1 and Collagen
Confluent bovine aortic endothelial cells (EC) were incubated with 22-OHC (25 µmol/L; H9384, Sigma) with and without L-4F (10 µg/mL) overnight and then prepared for (1) A23187 stimulated ·NO and O2· production as described,22,23 (2) Western blot analysis of ABCA-1 as described,12 or (3) measurements of collagen synthesis based on collagenase-sensitive [3H]proline incorporation as described by Siwik et al.24
MPO/ApoA-I and 3-Nitrotyrosine/ApoA-I
MPO association with apoA-I was determined by Western blot analysis of apoA-I immunoprecipitates (goat anti-mouse apoA-I, K59166G, Biodesign, Saco, Me) using a rabbit anti-mouse MPO antibody (07-009, Upstate Biomedical, Charlottesville, Va). 3-Nitrotyrosine (3NT) in apoA-I was determined by Western blot analysis of apoA-I immunoprecipitates using mouse anti-nitrotyrosine (05-233, Upstate Biomedical) and antiapoA-I (K59166G, Biodesign) as primary antibodies and the appropriate horseradish peroxidaseconjugated secondary antibodies as described.15 In both cases, apoA-I was detected by Western blot analysis using a rabbit anti-mouse apoA-I antibody (K23001R, Biodesign).
Statistical Analysis
Comparisons between 2 groups were by the Student t test. Comparisons between multiple groups were by 1-way ANOVA with Bonferroni correction for multiple groups. Comparisons between vasodilation curves were by 2-way ANOVA. Minimum levels of significance were set at P<0.05. Statistical analysis was performed using Prism 3 from GraphPad Software Inc.
| Results |
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To confirm vessels in Ldlr/ mice from group IV had preexisting disease, before D-4F treatments, we fed another set of Ldlr/ mice WD. Vasodilation was impaired in group V mice after 4 weeks of WD compared with vasodilation in group VI and group VII (Figure 2C). With just 2 weeks of oral D-4F treatments, concurrently with WD, vasodilation in group VI was improved beyond levels in Ldlr/ mice that were fed laboratory chow (group VII) (Figure 2C).
As a nonbiased measure of arterial structure, we simply determined the effects of D-4F on arterial wall thickening induced by WD by measuring inside and outside diameters of arteries after incubation with papaverine to eliminate any contribution of endothelial cell function/dysfunction to vessel diameter. Wall thickness in Ldlr/ mice fed WD was markedly increased compared with the wall thickness in C57BL/6 or Ldlr/ mice fed laboratory chow diet (Figure 3A). At all time points tested, oral D-4F reduced wall thickness in Ldlr/ mice fed WD regardless of duration of oral D-4F treatments (Figure 3B). Wall thickness data confirmed that the vessels in Ldlr/ mice from group IV had preexisting disease at 4 weeks of WD, before D-4F treatments (Figure 3C). More importantly, treating WD-fed Ldlr/ mice with D-4F for only 2 weeks, concurrently with WD, reduced wall thickness to essentially the same thickness as Ldlr/ mice fed laboratory chow (Figure 3C).
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D-4F had no effect on total cholesterol or HDL cholesterol in Ldlr/ mice fed WD (Table 1). Although there was a tendency for HDL levels to be higher in Ldlr/ mice fed WD and treated with D-4F, statistical significance was not achieved. In contrast to D-4F effects on cholesterol, proinflammatory HDL levels were significantly decreased.
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To determine mechanisms by which proinflammatory lipids impair endothelial cell function, we treated endothelial cell cultures with 22-OHC with and without L-4F. 22-OHC decreased stimulated ·NO production (Figure 4A) and increased stimulated O2· generation (Figure 4B). L-4F restored stimulated ·NO production (Figure 4A) while decreasing stimulated O2· production in the cultures treated with 22-OHC (Figure 4B). Western blot analysis confirms 22-OHC increased ABCA-1 expression by a liver X receptordependent mechanism, as was shown earlier by Reddy et al,12 which was unaltered by L-4F. Next, we examined effects of 22-OHC and L-4F on collagen production as a means of determining whether or not this oxysterol and apoA-I mimetic modulated endothelial cell matrix production. 22-OHC increased collagen synthesis, which L-4F reduced to control levels (Figure 4D).
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Plasma measurements of MPO revealed that D-4F had no effect on total MPO concentrations in Ldlr/ mice fed WD (Figure 5A). However, immunoblotting for MPO and 3NT in apoA-I of apoA-I immunoprecipitates from these mice revealed D-4F decreased both MPO association with and 3NT in apoA-I (Figure 5B and 5C). Immunoblots of apoA-I immunoprecipitates from C57BL/6 plasma that was treated with D-4F in vitro revealed D-4F had no direct effect on MPO association with apoA-I (Figure 5D).
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Next, we fed Ldlr//apoA-I/ mice WD and treated them with and without D-4F to determine the extent to which D-4F required HDL to improve vasodilation and/or reduce vessel wall thickness. Although ACh promoted a moderate increase in vasodilation in vessels from Ldlr//apoA-I/ mice fed WD, the upward slope of the ACh dose response curves in the presence of L-NAME revealed only a small portion of endothelium-dependent vasodilation in these mice was actually mediated by eNOS (Figure 6A). Comparing hatched regions in Figure 6A and 6B reveals D-4F increased eNOS-dependent vasodilation in the hypercholesterolemic Ldlr//apoA-I/ mice by nearly 2-fold. However, in hypercholesterolemic double-knockout mice, D-4F failed to decrease vessel wall thickness (Figure 6C). Analysis of plasma lipids reveals HDL cholesterol in the Ldlr//apoA-I/ mice (Table 2) was decreased compared with the concentrations in Ldlr/ mice (Table 1). D-4F had little effect on cholesterol in the hypercholesterolemic Ldlr//apoA-I/ mice but did increase HDL cholesterol (Table 2). More importantly, D-4F failed to protect HDL against oxidative modification in the double-knockout mice (Table 2), in contrast to its ability to protect HDL against oxidation in hypercholesterolemic Ldlr/ mice (Table 1).
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| Discussion |
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In the studies here, we assessed vessel wall architecture in the same vessel used to measure vasodilation. Therefore we could not perform histological analysis on these vessels. Instead, we relied on an unbiased assessment of wall thickness and explored potential mechanisms in endothelial cell cultures. Additional studies will be required to determine the precise cause of thickening of the facialis arteries in the future. In mechanistic studies, we showed that the proinflammatory oxysterol, 22-OHC, shifts ·NO and O2· balance and increases collagen synthesis, both common features in vessels with early lesions.27 More importantly, the ability of 4F to restore ·NO and O2· balance and reduce collagen production in 22-OHCtreated endothelial cell cultures is consistent with the marked increases in endothelium- and eNOS-dependent vasodilation and reductions in vessel wall thickness that we observed in hypercholesterolemic Ldlr/ mice treated with D-4F.
Mechanistically, many of our findings are consistent with the notion that D-4F binds8 and removes oxidized lipids to protect vascular endothelial cell function.28 As eNOS function (coupled and uncoupled activity) in endothelial cell cultures is dramatically altered by native LDL and oxidized LDL,23,29,30 logically, anything limiting vascular endothelial cell exposure to proinflammatory lipids should improve eNOS-dependent vasodilation. The fact 4F did not alter 22-OHC-induced increases in ABCA-1 expression suggests endothelial cells exposed to 22-OHC are under a constant state of oxidative stress even in the presence of 4F. Accordingly, the ability of 4F to restore ·NO balance and reduce collagen expression in 22-OHCtreated endothelial cells is likely related more to the ability of this apoA-I mimetic to bind oxidized phospholipids than oxysterols. If this is the case, then one can envision 22-OHC increasing endothelial cell production of oxidized phospholipids that, in turn, shift ·NO balance and increase collagen production. Further, 4F, via binding oxidized phospholipids, should limit this autocrine-type exposure to the very proinflammatory lipids inducing this prooxidant and inflammatory phenotype (ie,
O2·,
·NO, and increased collagen). Evidence supporting this hypothesis is the fact that 4F restored ·NO and O2· balance without altering expression of ABCA-1. The fact that 4F did not alter ABCA-1 expression is also important by itself, because ABCA-1 provides a means for endothelial cells subjected to oxidative stress to more easily rid themselves of oxidized phospholipids.12 As ABCA-1 activity can be impaired via oxidation,12 our findings demonstrate 4F represents a therapeutic agent that helps to preserve the critical function of ABCA-1 within the endothelium.
Probing mechanisms for D-4F protecting HDL against oxidative modification, we observed D-4F had no effect on total MPO concentrations in the plasma of hypercholesterolemic Ldlr/ mice, but did reduce MPO association with apoA-I and subsequent 3NT formation in apoA-I (an index of oxidative modification supporting our proinflammatory HDL findings). Such findings indicate that parallels do exist between the MPO-mediated mechanisms in mice and those in humans who have documented increased risk of heart disease.15 The fact that D-4F decreased MPO association with apoA-I in vivo but not in vitro suggests that the ability of D-4F to reduce MPO association with HDL in vivo is not attributable simply to displacement. It is possible that D-4F may also protect HDL indirectly by restoring ·NO and O2· balance to the endothelium,6,23 which should, in turn, decrease O2· and, subsequently, the H2O2 with which MPO nitrates tyrosine residues in apoA-I.15 Another possibility is that 4F increased extracellular superoxide dismutase, which should, in turn, decrease O2·, as shown in diabetic rats by Kruger et al.31
Our studies using the Ldlr//apoA-I/ mice and D-4F revealed some remarkable insight into the atheroprotective mechanisms of HDL. First, HDL deficient in apoA-I is more susceptible to oxidation than apoA-I containing HDL by a mechanism that cannot be counteracted by D-4F treatments. Second, expression of apoA-Ideficient HDL can be increased by D-4F, suggesting D-4F may upregulate expression of other apolipoprotein A proteins, as it has been shown for apoA-I.32 Third, the marked increase in proinflammatory HDL in Ldlr//apoA-I/ mice directly correlates with an increase in wall thickness in these animals, which is in direct contrast to the ability of D-4F to improve vasodilation. This disconnect between the ability of D-4F to improve vasodilation and reduce vessel wall thickness was unexpected. One explanation for the inability of D-4F to protect HDL against oxidative modification in the Ldlr//apoA-I/ mice is the relative rates of DCF fluorescence, an index of seeding molecules of lipid hydroperoxides in HDL,11 were 100 times greater in HDL from Ldlr//apoA-I/ mice than it was in HDL from Ldlr/ mice. Such large increases in proinflammatory HDL levels suggest 2 distinct possibilities: either apoA-I is essential for protecting HDL against oxidation and D-4F protects HDL against oxidation via interacting with apoA-I or the absolute amount of HDL plays a critical role in the mechanisms by which D-4F protects HDL against oxidation to reduce vessel wall thickness. Such observations are consistent with recent reports indicating cardiovascular events are mediated more by proinflammatory HDL than by total HDL,11,33 a report showing high concentrations of HDL are essential for reducing plaque growth in patients with preexisting carotid artery disease34 and our report showing 4F afforded greater protection in vivo than in vitro when compared with vessels preincubated with LDL.6
Perhaps D-4F was unable to interact with apoA-Ideficient HDL to bind and remove proinflammatory lipids that increase HDL susceptibility to oxidation.35 Alternatively, D-4F may interact directly with vascular endothelium to protect endothelial cell function as was recently shown by Gupta et al, where L-4F displaced lipopolysaccharide from vascular endothelium to preserve endothelial cell function.36 Another possibility is D-4F may act preferentially with vascular endothelial cells rather than vascular smooth muscle cells, which on exposure to oxidized LDL, express less matrix metalloproteases, which is considered to increase matrix deposition.37 Such questions, although important, must remain unanswered until more mechanistic studies can be performed.
In conclusion, D-4F reduces proinflammatory HDL levels in hypercholesterolemic Ldlr/ mice but not Ldlr//apoA-I/ fed WD. The antiatherogenic properties of D-4F appear to go hand-in-hand with the ability of the apoA-I mimetic to reduce vessel wall thickness early on and then, with longer treatments, increase vasodilation to almost control levels in Ldlr/ mice. Our studies suggest the mechanisms mediating impaired vasodilation in this early model of vascular disease may be different from those mediating vessel wall thickness. If this is the case, then HDL with the proper apolipoprotein composition and/or a critical concentration of HDL may be required for D-4F to be able to both reduce wall thickness and improve vasodilation. Finally, our findings suggest D-4F may be useful for treatment of arteries with preexisting disease.
| Acknowledgments |
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| Footnotes |
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*Both authors contributed equally to the experimental design of this study. ![]()
Original received August 4, 2005; revision received September 30, 2005; accepted October 3, 2005.
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D. Weihrauch, H. Xu, Y. Shi, J. Wang, J. Brien, D. W. Jones, S. Kaul, R. A. Komorowski, M. E. Csuka, K. T. Oldham, et al. Effects of D-4F on vasodilation, oxidative stress, angiostatin, myocardial inflammation, and angiogenic potential in tight-skin mice Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1432 - H1441. [Abstract] [Full Text] [PDF] |
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S. J. Peterson, D. Husney, A. L. Kruger, R. Olszanecki, F. Ricci, L. F. Rodella, A. Stacchiotti, R. Rezzani, J. A. McClung, W. S. Aronow, et al. Long-Term Treatment with the Apolipoprotein A1 Mimetic Peptide Increases Antioxidants and Vascular Repair in Type I Diabetic Rats J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 514 - 520. [Abstract] [Full Text] [PDF] |
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N. M. Gharavi, P. S. Gargalovic, I. Chang, J. A. Araujo, M. J. Clark, W. L. Szeto, A. D. Watson, A. J. Lusis, and J. A. Berliner High-Density Lipoprotein Modulates Oxidized Phospholipid Signaling in Human Endothelial Cells From Proinflammatory to Anti-inflammatory Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1346 - 1353. [Abstract] [Full Text] [PDF] |
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G. M. Buga, J. S. Frank, G. A. Mottino, M. Hendizadeh, A. Hakhamian, J. H. Tillisch, S. T. Reddy, M. Navab, G. M. Anantharamaiah, L. J. Ignarro, et al. D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet J. Lipid Res., October 1, 2006; 47(10): 2148 - 2160. [Abstract] [Full Text] [PDF] |
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C. Mineo, H. Deguchi, J. H. Griffin, and P. W. Shaul Endothelial and Antithrombotic Actions of HDL Circ. Res., June 9, 2006; 98(11): 1352 - 1364. [Abstract] [Full Text] [PDF] |
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M. Navab, G.M. Anantharamaiah, and A. M. Fogelman An Apolipoprotein A-I Mimetic Works Best in the Presence of Apolipoprotein A-I Circ. Res., November 25, 2005; 97(11): 1085 - 1086. [Full Text] [PDF] |
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