This Article Abstract Full Text (PDF) All Versions of this Article: 107/23/2944    most recent 01.CIR.0000070934.69310.1Av1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bisoendial, R. J. Articles by Stroes, E. S.G. Search for Related Content PubMed PubMed Citation Articles by Bisoendial, R. J. Articles by Stroes, E. S.G. Related Collections Lipids Lipid and lipoprotein metabolism Endothelium/vascular type/nitric oxide Risk Factors

(Circulation. 2003;107:2944.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Restoration of Endothelial Function by Increasing High-Density Lipoprotein in Subjects With Isolated Low High-Density Lipoprotein

Radjesh J. Bisoendial, MD; G. Kees Hovingh, MD; Johannes H.M. Levels, PhD; Peter G. Lerch, PhD; Irmgard Andresen, MD, PhD; Michael R. Hayden, MB, ChB, PhD; John J.P. Kastelein, MD, PhD; Erik S.G. Stroes, MD, PhD

From the Department of Vascular Medicine, Academic Medical Centre, Amsterdam, Netherlands (R.J.B., G.K.H., J.H.M.L., J.J.P.K., E.S.G.S.); ZLB Bioplasma AG, Bern, Switzerland (P.G.L., I.A.); and the Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada (M.R.H.).

Correspondence to John J.P. Kastelein, MD, PhD, Department of Vascular Medicine, G1.146, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail e.s.stroes{at}amc.uva.nl

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— Loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene locus are the underlying cause for familial hypoalphalipoproteinemia, providing a human isolated low-HDL model. In these familial hypoalphalipoproteinemia subjects, we evaluated the impact of isolated low HDL on endothelial function and the vascular effects of an acute increase in HDL.

Methods and Results— In 9 ABCA1 heterozygotes and 9 control subjects, vascular function was assessed by venous occlusion plethysmography. Forearm blood flow responses to the endothelium-dependent and -independent vasodilators serotonin (5HT) and sodium nitroprusside, respectively, and the inhibitor of nitric oxide synthase N^G-monomethyl-L-arginine (L-NMMA) were measured. Dose-response curves were repeated after systemic infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) disks. At baseline, ABCA1 heterozygotes had decreased HDL levels (0.4±0.2 mmol/L; P<0.05), and their forearm blood flow responses to both 5HT (maximum, 49.0±10.4%) and L-NMMA (maximum, -22.8±22.9%) were blunted compared with control subjects (both P≤0.005). Infusion of apoA-I/PC disks increased plasma HDL to 1.3±0.4 mmol/L in ABCA1 heterozygotes, which resulted in complete restoration of vasomotor responses to both 5HT and L-NMMA (both P≤0.001). Endothelium-independent vasodilation remained unaltered throughout the protocol.

Conclusions— In ABCA1 heterozygotes, isolated low HDL is associated with endothelial dysfunction, attested to by impaired basal and stimulated NO bioactivity. Strikingly, both parameters were completely restored after a single, rapid infusion of apoA-I/PC. These findings indicate that in addition to its long-term role within reverse cholesterol transport, HDL per se also exerts direct beneficial effects on the arterial wall.

Key Words: lipoproteins • apolipoproteins • endothelium • nitric oxide

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Despite a clinically significant reduction in coronary event rates after the use of statins, both primary and secondary prevention trials indicate that 60% to 70% of major cardiovascular events cannot be prevented with current therapeutic strategies. This has prompted the search for novel drug targets to further improve cardiovascular outcome. Among these options, strategies aiming at increasing HDL levels hold great promise.^1–3 In this respect, a strong inverse relationship has been established between HDL levels and the incidence of coronary artery disease.⁴ In line with this, the prevalence of HDL deficiency (<35 mg/dL) in men with premature coronary artery disease reaches up to 40%.^5,6 Nevertheless, the implications of increasing HDL levels for cardiovascular outcome remain to be determined. The fact that low HDL is often associated with other risk factors, such as enhanced triglyceride levels and insulin resistance (composing the metabolic syndrome), suggests that those, instead of low HDL per se, might be primarily responsible for the observed relationship with cardiovascular events. This has promoted the search for human models with an isolated low-HDL phenotype in which the consequences of isolated low HDL and pharmacological modalities targeting HDL for endothelial phenotype and cardiovascular outcome can be studied.

A proper model is familial hypoalphalipoproteinemia, which was recently found to result from loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene. Heterozygous carriers are characterized by a moderate to severe decrease of HDL but have normal levels of apolipoprotein B (apoB)–containing lipoproteins, thus enabling assessment of the role of isolated low HDL in vivo.⁷ Because the initial step in the reverse cholesterol transport (RCT) pathway is impeded in these individuals, cell-derived cholesterol accumulates within the arterial wall, clinically manifested by advanced carotid intima-media thickening and markedly increased susceptibility to atherosclerosis.^8,9

Endothelium-derived nitric oxide (NO) has emerged as a pivotal antiatherogenic mediator. Diminished NO bioavailability is a hallmark of (early) atherosclerosis, which can be measured indirectly in patients as impaired endothelium-dependent vasomotor response.¹⁰ In this respect, endothelial vasodilator dysfunction has been demonstrated in subjects with established coronary risk factors even before the onset of morphological changes, although most studies have indicated its reversibility after risk factor exclusion.^11–14 More recently, the predictive value of endothelial vasodilator dysfunction for future cardiovascular events has been underscored by several research groups.^15–18

In the present study, we evaluated the consequences of isolated low HDL for vascular function in subjects carrying heterozygous ABCA1 gene mutations compared with normolipidemic sex- and age-matched control subjects (controls). Previous data in these individuals, including accelerated carotid atherogenesis, suggested a priori compromised endothelial function. Subsequently, we determined whether an acute increase in HDL level (on infusion of apolipoprotein A-I/phosphatidylcholine [apoA-I/PC] disks) would translate into an improvement of vascular function.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Subjects
Nine ABCA1 heterozygotes (6 men and 3 women; mean [±SD] age, 42.9±13.9 years) and 9 age- and sex-matched normolipidemic controls (6 men and 3 women; mean [±SD] age, 46.1±13.5 years) were enrolled in the study. Affected subjects were selected from available family members of 4 Dutch kindreds with known mutations on the ABCA1 gene locus, as described previously.¹¹ At baseline, HDL cholesterol levels were 0.5±0.2 versus 1.2±0.3 mmol/L (P<0.05) in the control group. Four subjects were smokers, equally divided between the 2 groups (Table 1). All subjects had normal plasma levels of apoB-containing lipoproteins (total cholesterol, LDL, or triglycerides below the 95th percentile), whereas none of the subjects had diabetes mellitus, hypertension (defined as systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg), or congestive heart failure. Before entering the study, subjects discontinued all lipid-lowering medication for a period of ≥6 weeks. All subjects refrained from alcohol, tobacco, and caffeine-containing drinks for more than 12 hours before the study. The study protocol was approved by the Institutional Review Board at the Academic Medical Center, University Hospital of Amsterdam. All subjects gave written informed consent.

View this table: [in this window] [in a new window]   TABLE 1. Demographic and Baseline Parameters of the Study Cohort

Study Protocol
Assessment of vascular function was performed at baseline and after apoA-I/PC infusion by use of venous occlusion strain-gauge plethysmography (EC4; Hokanson Inc). All experiments were performed in a quiet, air-conditioned room (temperature, 22°C to 24°C), with the subjects in the supine position throughout the study. The nondominant brachial artery was cannulated with a 20-gauge polyethylene catheter under local anesthesia, and blood was drawn for baseline measurements. Insertion was followed by a 20-minute interval for the artery to reestablish baseline conditions. Thereafter, forearm blood flow (FBF), expressed in milliliters per minute per 100 mL of forearm tissue volume (FAV), was measured simultaneously in both arms. During each measurement, blood pressure cuffs around both upper arms were inflated (40 mm Hg) by use of a rapid cuff inflator. Simultaneously, bilateral wrist cuffs were inflated to above-systolic blood pressure to exclude hand circulation (200 mm Hg). Intra-arterial blood pressure and heart rate were monitored continuously. Next, FBF response to cumulative doses of the endothelium-dependent vasodilator serotonin (5HT, Sigma; 0.6, 1.8, and 6 ng · 100 mL FAV^-1 · min^-1), the endothelium-independent vasodilator sodium nitroprusside (SNP, Spruyt Hillen; 6, 60, 180, and 600 ng · 100 mL FAV^-1 · min^-1), and the competitive inhibitor of endothelial NO synthase (eNOS) N^G-monomethyl-L-arginine (L-NMMA, Kordia; 50, 100, 200, and 400 µg · 100 mL FAV^-1 · min^-1) was measured. All agents were administered intra-arterially for 6, 4, and 8 minutes at each dose, respectively, with a constant-rate infusion pump. Six measurements during the last 2 minutes (steady state) were averaged to determine mean FBF. The 3 different infusion blocks proceeded after a 15-minute rest period or until FBF had returned to baseline. Then, a venous catheter was inserted in the contralateral arm for systemic administration of apoA-I/PC disks at a dose of 80 mg/kg body weight over a period of 4 hours (ZLB Bioplasma AG).^19,20 Subsequently, all 3 infusion blocks were repeated.

Biochemical Analysis
Blood samples were drawn from the subjects after a 12-hour overnight fast, immediately and 3 hours after apoA-I/PC infusion. After centrifugation within 1 hour after collection, aliquots were snap-frozen in liquid nitrogen and stored at -80°C until the assays were performed. All measurements were performed at the vascular and clinical laboratory of the Academic Medical Center, University Hospital of Amsterdam. Liver transaminases were measured with standard laboratory methods. Plasma triglycerides, total cholesterol, and LDL and HDL levels were determined with high-performance gel permeation chromatography.²¹ In brief, the system contained a PU-980 ternary pump with an LG-980-02 linear degasser and an FP-920 fluorescence and UV-975 UV/VIS detector (Jasco). An extra P-50 pump (Pharmacia Biotech) was used for addition of in-line cholesterol (or triglyceride) PAP enzymatic reagent (Biomerieux) at 0.1 mL/min. EDTA plasma was diluted 1:1 with Tris-buffered saline, and 30 µL of a sample/buffer mixture was loaded on a Superose 6 HR 10/30 column (Pharmacia Biotech) for lipoprotein separation at a flow rate of 0.31 mL/min. Plasma levels of apoB and apoA-I were assayed on stored plasma by rate nephelometry. The serum concentration of malondialdehyde-modified LDL was assayed by a murine monoclonal antibody 4E6–based sandwich ELISA (Mercodia AB) as described previously.²²

Statistical Analysis
All results of clinical parameters, including plethysmographic data, are expressed as mean±SD. Descriptive statistics between the 2 groups were compared by means of 2-tailed paired or unpaired Student’s t test. FBF was averaged over 6 consecutive recordings during the last 2 minutes of each infusion. Statistical analysis of FBF measurements for individual subjects between the 2 groups was performed by 2-way ANOVA for repeated measures. A probability value of P<0.05 was considered significant and a value of P<0.01 as highly significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Baseline clinical characteristics of the ABCA1 heterozygotes and control subjects are summarized in Table 1. HDL levels were significantly lower in ABCA1 heterozygotes than in controls (P<0.05). Other lipid parameters, as well as systolic and diastolic blood pressures and body mass index, were not significantly different. After apoA-I/PC infusion, plasma HDL cholesterol increased from 0.4±0.3 to 1.3±0.4 mmol/L and from 1.0±0.3 to 2.1±0.5 mmol/L in ABCA1 heterozygotes and controls, respectively (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Laboratory Parameters of the Study Cohort

Effects of ApoA-I/PC Infusion on eNOS Activity
At baseline, the vasoconstrictor response to L-NMMA, reflecting basal NO activity, was blunted in ABCA1 heterozygotes compared with controls (P=0.001; Figure 1). After a single rapid infusion of apoA-I/PC disks, the L-NMMA constrictor response was increased significantly (P=0.001; Figure 1), reaching levels comparable to those of control subjects. In contrast, apoA-I/PC infusion had no effect on L-NMMA response in control subjects (Figure 1).

View larger version (21K): [in this window] [in a new window]   Figure 1. L-NMMA induced vasoconstriction before and after HDL increase. FBF dose-response curves to inhibitor of NOS L-NMMA before () and after () apoA-I/PC infusion in ABCA1 heterozygotes and normocholesterolemic controls (before, ; after, ). L-NMMA–induced vasoconstriction at baseline was blunted in ABCA1 mutation carriers compared with control subjects (*P=0.001). After HDL increase by apoA-I/PC infusion, FBF response to L-NMMA in ABCA1 heterozygotes normalized completely (P=0.001).

Intra-arterial infusion of the endothelium-dependent vasodilator 5HT increased FBF in a dose-dependent manner in the 2 groups. At baseline, the FBF response to 5HT was impaired significantly in ABCA1 heterozygotes compared with controls (P<0.0001; Figure 2). After apoA-I/PC infusion, FBF response to 5HT increased significantly to levels comparable to those of control responses (P<0.001; Figure 2). In line with L-NMMA data, apoA-I/PC infusion had no effect on 5HT-induced vasodilator responses in control subjects (Figure 2).

View larger version (20K): [in this window] [in a new window]   Figure 2. 5HT-induced vasodilation before and after HDL increase. FBF dose-response curves to endothelium-dependent vasodilator serotonin (5-HT) before () and after () apoA-I/PC infusion in ABCA1 heterozygotes and normocholesterolemic controls (before, ; after, ). Endothelium-dependent vasodilation to 5-HT at baseline was attenuated in ABCA1 heterozygotes compared with control subjects (*P<0.0001). After HDL increase by apoA-I/PC infusion, FBF response to 5HT in ABCA1 mutation carriers normalized completely (P<0.001).

At baseline, endothelium-independent vasodilation in response to SNP was not different between ABCA1 heterozygotes and controls, and apoA-I/PC infusion likewise showed no effect on the SNP vasodilator response in either group (Figure 3).

View larger version (17K): [in this window] [in a new window]   Figure 3. SNP-induced vasodilation before and after HDL increase. FBF dose-response curves to endothelium-independent vasodilator SNP before and after apoA-I/PC infusion in ABCA1 heterozygotes and normocholesterolemic controls. At baseline, SNP-induced vasodilator response was not different between ABCA1 heterozygotes and controls (P=0.30) and remained unaltered by apoA-I/PC infusion.

Biochemistry
Circulating levels of oxidized LDL were not significantly different between ABCA1 heterozygotes and controls. Also, the levels of these parameters remained unaltered after apoA-I/PC infusion.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present study, we show that both basal and stimulated NO activity is sharply reduced in ABCA1 heterozygotes compared with age- and sex-matched controls. Strikingly, an increase in HDL by a single, rapid infusion of apoA-I/PC disks results in complete recovery of endothelial vasomotor response. These novel data indicate that isolated low HDL in ABCA1 heterozygotes is associated with endothelial dysfunction, which is entirely reversible on HDL increase.

The ABCA1 transporter facilitates apoA-I–mediated transfer of cellular cholesterol and phospholipids from the plasma membrane to poorly lipidated (apo)lipoproteins. Loss of ABCA1 function leads to defective lipidation, resulting in enhanced clearance of the HDL precursor fraction, with ensuing low plasma HDL levels.^7,8 We recently demonstrated that heterozygous carriers of ABCA1 gene mutations are characterized by advanced arterial wall thickening and an increased risk for early-onset coronary artery disease. The correlation between their cholesterol efflux rates and arterial wall thickness suggests a critical role for the impairment of the apoA-I/RCT pathway in mediating these changes in vascular morphology.

In this study, we also show an impairment in both basal and stimulated NO bioavailability, which is completely reversible on HDL increase. The observed vascular effects shortly after HDL increase seem less likely to be related to the RCT pathway, for 2 reasons. First, ABCA1 heterozygotes are characterized by a significantly impaired RCT pathway in which the apoA-I concentration is not the rate-limiting factor.²³ Second, vascular effects as a result of modulating the apoA-I/RCT pathway are not expected to occur that soon, because cholesterol is mobilized primarily from easily mobilizable stores, eg, liver and spleen.^8,24 Hence, these data suggest that HDL by itself is a potent regulator of the endothelial NO pathway in vivo.

The interactions between (low) HDL and endothelial NO bioavailability can be explained by several mechanisms. First, because the localization of eNOS in cholesterol-rich microdomains of the plasma membrane (including caveolae) is critical for its activation, caveolar disruption has a profound effect on endothelial NO release.²⁵ Recently, caveolar processing was shown to be disturbed in ABCA1-defective human fibroblasts, resulting in a substantial decrease in the number of caveolae on the plasma membrane.²⁶ Given that ABCA1 is also present in endothelial cells, similar processes are likely to contribute to the impaired eNOS functionality.^27,28 Next, low HDL may be associated with increased vascular oxidative stress, secondarily contributing to impaired endothelial NO bioavailability. Partially because of the presence of the enzymes paraoxonase and platelet-activating factor hydrolase, HDL has been found to exert potent antioxidant effects.^29,30 In line with this, infusion of apoA-I/PC disks, as in our protocol, resulted in a decreased susceptibility to oxidation of LDL in humans. However, in the present study, we were unable to find support for a pro-oxidant state in ABCA1 heterozygotes, because oxidized LDL levels were not significantly higher, nor were they altered on apoA-I/PC infusion. Third, recent data have elegantly shown a direct stimulatory effect of HDL on eNOS via a scavenger receptor, class B, type I–dependent pathway.^31–33 In particular, the low basal NO activity in the ABCA1 heterozygotes may support a physiological role of HDL as a direct regulator of eNOS activity in vivo.

Infusion of apoA-I/PC promotes intravascular generation of nascent HDL, which has a natural course in humans.²⁴ Subsequently, HDL increase may contribute to improvement of endothelial vasomotor function by several mechanisms. First, recent data have shown acute stimulatory effects of apoA-I on intracellular cholesterol trafficking from the Golgi apparatus to the cell surface in human fibroblasts,³⁴ resulting in a rapid increase in the number of membrane caveolae. Theoretically, in these ABCA1 heterozygotes, apoA-I may have initiated restoration of intracellular events involving caveolar processing, with subsequent reshuttling of eNOS to caveolar regions in endothelial cells. Finally, along with the aforementioned direct eNOS-regulating mechanisms, an increase in apoA-I–containing HDLs may have resulted in enhanced eNOS activity, as attested to in particular by augmented basal NO bioavailability.

Clinical Perspectives
In the present study, we show that low HDL by itself can be independently responsible for adverse cardiovascular effects, assessed as endothelial dysfunction. Importantly, the reversibility of vascular dysfunction in low-HDL patients on acute HDL increase constitutes a powerful stimulus for ongoing efforts targeting HDL increase as a tool in cardiovascular prevention. The present findings not only underscore the beneficial cardiovascular potential with regard to the endothelium but also indicate that endothelial function testing is a suitable intermediate end point in future trials evaluating the effects of HDL increase on cardiovascular disease progression.

	Acknowledgments

 
Dr Kastelein is an established investigator of the Netherlands Heart Foundation (2000D039). Dr Hovingh is supported by the Netherlands Heart Foundation (2000.115). Information on ABCA1 gene mutations was obtained through a collaboration with Xenon Genetics Inc. We thank R.J. Berckmans, K. Bakhtiari, and B. Karstenkov (Department of Clinical Chemistry and Vascular Medicine, AMC Hospital, Amsterdam) for laboratory support.

Received February 5, 2003; accepted March 4, 2003.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Garber DW, Datta G, Chaddha M, et al. A new synthetic class A amphipathic peptide analogue protects mice from diet-induced atherosclerosis. J Lipid Res. 2001; 42: 545–552.[Abstract/Free Full Text]
   
2. Spieker LE, Sudano I, Hurlimann D, et al. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation. 2002; 105: 1399–1402.[Abstract/Free Full Text]
   
3. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 2002; 105: 2159–2165.[Abstract/Free Full Text]
   
4. Gordon DJ, Rifkind BM. High-density lipoprotein: the clinical implications of recent studies. N Engl J Med. 1989; 321: 1311–1316.[Medline] [Order article via Infotrieve]
   
5. Maron DJ. The epidemiology of low levels of high-density lipoprotein cholesterol in patients with and without coronary artery disease. Am J Cardiol. 2000; 86: 11L–14L.[CrossRef][Medline] [Order article via Infotrieve]
   
6. Rubins HB, Robins SJ, Collins D, et al. Distribution of lipids in 8,500 men with coronary artery disease. Department of Veterans Affairs HDL Intervention Trial Study Group. Am J Cardiol. 1995; 75: 1196–1201.[CrossRef][Medline] [Order article via Infotrieve]
   
7. Brooks-Wilson A, Marcil M, Clee SM, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999; 22: 336–345.[CrossRef][Medline] [Order article via Infotrieve]
   
8. Clee SM, Kastelein JJ, van Dam M, et al. Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. J Clin Invest. 2000; 106: 1263–1270.[Medline] [Order article via Infotrieve]
   
9. van Dam MJ, de Groot E, Clee SM, et al. Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study. Lancet. 2002; 359: 37–42.[CrossRef][Medline] [Order article via Infotrieve]
   
10. Stroes ES, van Faassen EE, Yo M, et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res. 2000; 86: 1129–1134.[Abstract/Free Full Text]
    
11. Stroes ES, Koomans HA, de Bruin TW, et al. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet. 1995; 346: 467–471.[CrossRef][Medline] [Order article via Infotrieve]
    
12. Park JB, Charbonneau F, Schiffrin EL. Correlation of endothelial function in large and small arteries in human essential hypertension. J Hypertens. 2001; 19: 415–420.[CrossRef][Medline] [Order article via Infotrieve]
    
13. Clarkson P, Celermajer DS, Powe AJ, et al. Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease. Circulation. 1997; 96: 3378–3383.[Medline] [Order article via Infotrieve]
    
14. Gaenzer H, Neumayr G, Marschang P, et al. Effect of insulin therapy on endothelium-dependent dilation in type 2 diabetes mellitus. Am J Cardiol. 2002; 89: 431–434.[CrossRef][Medline] [Order article via Infotrieve]
    
15. Suwaidi JA, Hamasaki S, Higano ST, et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000; 101: 948–954.[Medline] [Order article via Infotrieve]
    
16. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000; 101: 1899–1906.[Medline] [Order article via Infotrieve]
    
17. Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002; 106: 653–658.[CrossRef][Medline] [Order article via Infotrieve]
    
18. Gokce N, Keaney JF Jr, Hunter LM, et al. Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation. 2002; 105: 1567–1572.[Abstract/Free Full Text]
    
19. Pajkrt D, Doran JE, Koster F, et al. Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia. J Exp Med. 1996; 184: 1601–1608.[Abstract/Free Full Text]
    
20. Lerch PG, Fortsch V, Hodler G, et al. Production and characterization of a reconstituted high density lipoprotein for therapeutic applications. Vox Sang. 1996; 71: 155–164.[CrossRef][Medline] [Order article via Infotrieve]
    
21. Levels JH, Abraham PR, van den EA, et al. Distribution and kinetics of lipoprotein-bound endotoxin. Infect Immun. 2001; 69: 2821–2828.[Abstract/Free Full Text]
    
22. Holvoet P, Collen D, Van de WF. Malondialdehyde-modified LDL as a marker of acute coronary syndromes. JAMA. 1999; 281: 1718–1721.[Abstract/Free Full Text]
    
23. Brousseau ME, Eberhart GP, Dupuis J, et al. Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size. J Lipid Res. 2000; 41: 1125–1135.[Abstract/Free Full Text]
    
24. Nanjee MN, Cooke CJ, Garvin R, et al. Intravenous apoA-I/lecithin discs increase pre-beta-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans. J Lipid Res. 2001; 42: 1586–1593.[Abstract/Free Full Text]
    
25. Govers R, Rabelink TJ. Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol. 2001; 280: F193–F206.[Abstract/Free Full Text]
    
26. Orso E, Broccardo C, Kaminski WE, et al. Transport of lipids from Golgi to plasma membrane is defective in Tangier disease patients and Abc1-deficient mice. Nat Genet. 2000; 24: 192–196.[CrossRef][Medline] [Order article via Infotrieve]
    
27. Fielding PE, Nagao K, Hakamata H, et al. A two-step mechanism for free cholesterol and phospholipid efflux from human vascular cells to apolipoprotein A-1. Biochemistry. 2000; 39: 14113–14120.[CrossRef][Medline] [Order article via Infotrieve]
    
28. Liao H, Langmann T, Schmitz G, et al. Native LDL upregulation of ATP-binding cassette transporter-1 in human vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2002; 22: 127–132.[Abstract/Free Full Text]
    
29. Navab M, Hama SY, Cooke CJ, et al. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1. J Lipid Res. 2000; 41: 1481–1494.[Abstract/Free Full Text]
    
30. Navab M, Hama SY, Anantharamaiah GM, et al. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res. 2000; 41: 1495–1508.[Abstract/Free Full Text]
    
31. Uittenbogaard A, Shaul PW, Yuhanna IS, et al. High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae. J Biol Chem. 2000; 275: 11278–11283.[Abstract/Free Full Text]
    
32. Yuhanna IS, Zhu Y, Cox BE, et al. High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat Med. 2001; 7: 853–857.[CrossRef][Medline] [Order article via Infotrieve]
    
33. Li XA, Titlow WB, Jackson BA, et al. High density lipoprotein binding to scavenger receptor, class B, type I activates endothelial nitric-oxide synthase in a ceramide-dependent manner. J Biol Chem. 2002; 277: 11058–11063.[Abstract/Free Full Text]
    
34. Sviridov D, Fidge N, Beaumier-Gallon G, et al. Apolipoprotein A-I stimulates the transport of intracellular cholesterol to cell-surface cholesterol-rich domains (caveolae). Biochem J. 2001; 358: 79–86.[CrossRef][Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				D J Hausenloy and D M Yellon Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels Heart, June 1, 2008; 94(6): 706 - 714. [Abstract] [Full Text] [PDF]

				M. Gomaraschi, D. Baldassarre, M. Amato, S. Eligini, P. Conca, C. R. Sirtori, G. Franceschini, and L. Calabresi Normal Vascular Function Despite Low Levels of High-Density Lipoprotein Cholesterol in Carriers of the Apolipoprotein A-IMilano Mutant Circulation, November 6, 2007; 116(19): 2165 - 2172. [Abstract] [Full Text] [PDF]

				O. van Oostrom, M. Nieuwdorp, P.E. Westerweel, I.E. Hoefer, R. Basser, E.S.G. Stroes, and M.C. Verhaar Reconstituted HDL Increases Circulating Endothelial Progenitor Cells in Patients With Type 2 Diabetes Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1864 - 1865. [Full Text] [PDF]

				L. Persegol, B. Verges, P. Gambert, and L. Duvillard Inability of HDL from abdominally obese subjects to counteract the inhibitory effect of oxidized LDL on vasorelaxation J. Lipid Res., June 1, 2007; 48(6): 1396 - 1401. [Abstract] [Full Text] [PDF]

				J.-C. Tardif, J. Gregoire, P. L. L'Allier, R. Ibrahim, J. Lesperance, T. M. Heinonen, S. Kouz, C. Berry, R. Basser, M.-A. Lavoie, et al. Effects of Reconstituted High-Density Lipoprotein Infusions on Coronary Atherosclerosis: A Randomized Controlled Trial JAMA, April 18, 2007; 297(15): 1675 - 1682. [Abstract] [Full Text] [PDF]

				C. R. Sirtori HDL and the progression of atherosclerosis: new insights Eur. Heart J. Suppl., October 1, 2006; 8(suppl_F): F4 - F9. [Abstract] [Full Text] [PDF]

				G. Theilmeier, C. Schmidt, J. Herrmann, P. Keul, M. Schafers, I. Herrgott, J. Mersmann, J. Larmann, S. Hermann, J. Stypmann, et al. High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P3 Lysophospholipid Receptor Circulation, September 26, 2006; 114(13): 1403 - 1409. [Abstract] [Full Text] [PDF]

				A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]

				S. J. Nicholls, E. M. Tuzcu, I. Sipahi, P. Schoenhagen, and S. E. Nissen Intravascular Ultrasound in Cardiovascular Medicine Circulation, July 25, 2006; 114(4): e55 - e59. [Full Text] [PDF]

				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]

				C. Mineo and P. W. Shaul Circulating cardiovascular disease risk factors and signaling in endothelial cell caveolae Cardiovasc Res, April 1, 2006; 70(1): 31 - 41. [Abstract] [Full Text] [PDF]

				K. J. Mukamal, M. K. Jensen, M. Gronbaek, M. J. Stampfer, J. E. Manson, T. Pischon, and E. B. Rimm Drinking Frequency, Mediating Biomarkers, and Risk of Myocardial Infarction in Women and Men Circulation, September 6, 2005; 112(10): 1406 - 1413. [Abstract] [Full Text] [PDF]

				R. J. Bisoendial, G. K. Hovingh, K. El Harchaoui, J. H.M. Levels, S. Tsimikas, K. Pu, A. E. Zwinderman, J. A. Kuivenhoven, J. J.P. Kastelein, and E. S.G. Stroes Consequences of Cholesteryl Ester Transfer Protein Inhibition in Patients With Familial Hypoalphalipoproteinemia Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): e133 - e134. [Full Text] [PDF]

				G. K. Hovingh, B. A. Hutten, A. G. Holleboom, W. Petersen, P. Rol, A. Stalenhoef, A. H. Zwinderman, E. de Groot, J. J.P. Kastelein MD, and J. A. Kuivenhoven Compromised LCAT Function Is Associated With Increased Atherosclerosis Circulation, August 9, 2005; 112(6): 879 - 884. [Abstract] [Full Text] [PDF]

				S. J. Nicholls, G. J. Dusting, B. Cutri, S. Bao, G. R. Drummond, K.-A. Rye, and P. J. Barter Reconstituted High-Density Lipoproteins Inhibit the Acute Pro-Oxidant and Proinflammatory Vascular Changes Induced by a Periarterial Collar in Normocholesterolemic Rabbits Circulation, March 29, 2005; 111(12): 1543 - 1550. [Abstract] [Full Text] [PDF]

				G. J. de Grooth, A. H. E. M. Klerkx, E. S. G. Stroes, A. F. H. Stalenhoef, J. J. P. Kastelein, and J. A. Kuivenhoven A review of CETP and its relation to atherosclerosis J. Lipid Res., November 1, 2004; 45(11): 1967 - 1974. [Abstract] [Full Text] [PDF]

				P. J. Barter, S. Nicholls, K.-A. Rye, G.M. Anantharamaiah, M. Navab, and A. M. Fogelman Antiinflammatory Properties of HDL Circ. Res., October 15, 2004; 95(8): 764 - 772. [Abstract] [Full Text] [PDF]

				M. Navab, G. M. Ananthramaiah, S. T. Reddy, B. J. Van Lenten, B. J. Ansell, G. C. Fonarow, K. Vahabzadeh, S. Hama, G. Hough, N. Kamranpour, et al. Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL J. Lipid Res., June 1, 2004; 45(6): 993 - 1007. [Abstract] [Full Text] [PDF]

				B. G. Drew, N. H. Fidge, G. Gallon-Beaumier, B. E. Kemp, and B. A. Kingwell High-density lipoprotein and apolipoprotein AI increase endothelial NO synthase activity by protein association and multisite phosphorylation PNAS, May 4, 2004; 101(18): 6999 - 7004. [Abstract] [Full Text] [PDF]

				H. Viswambharan, X.-F. Ming, S. Zhu, A. Hubsch, P. Lerch, G. Vergeres, S. Rusconi, and Z. Yang Reconstituted High-Density Lipoprotein Inhibits Thrombin-Induced Endothelial Tissue Factor Expression Through Inhibition of RhoA and Stimulation of Phosphatidylinositol 3-Kinase but not Akt/Endothelial Nitric Oxide Synthase Circ. Res., April 16, 2004; 94(7): 918 - 925. [Abstract] [Full Text] [PDF]

				G. A. Kaysen and J. P. Eiserich The Role of Oxidative Stress-Altered Lipoprotein Structure and Function and Microinflammation on Cardiovascular Risk in Patients with Minor Renal Dysfunction J. Am. Soc. Nephrol., March 1, 2004; 15(3): 538 - 548. [Abstract] [Full Text] [PDF]

				R. R. Singaraja, L. R. Brunham, H. Visscher, J. J.P. Kastelein, and M. R. Hayden Efflux and Atherosclerosis: The Clinical and Biochemical Impact of Variations in the ABCA1 Gene Arterioscler. Thromb. Vasc. Biol., August 1, 2003; 23(8): 1322 - 1332. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 107/23/2944    most recent 01.CIR.0000070934.69310.1Av1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions