Effect of two lipid-lowering strategies on high-density lipoprotein function and some HDL-related proteins: a randomized clinical trial

Chan Joo Lee, Seungbum Choi, Dong Huey Cheon, Kyeong Yeon Kim, Eun Jeong Cheon, Soo-Jin Ann, Hye-Min Noh, Sungha Park, Seok-Min Kang, Donghoon Choi, Ji Eun Lee, Sang-Hak Lee, Chan Joo Lee, Seungbum Choi, Dong Huey Cheon, Kyeong Yeon Kim, Eun Jeong Cheon, Soo-Jin Ann, Hye-Min Noh, Sungha Park, Seok-Min Kang, Donghoon Choi, Ji Eun Lee, Sang-Hak Lee

Abstract

Background: The influence of lipid-lowering therapy on high-density lipoprotein (HDL) is incompletely understood. We compared the effect of two lipid-lowering strategies on HDL functions and identified some HDL-related proteins.

Methods: Thirty two patients were initially screened and HDLs of 21 patients were finally analyzed. Patients were randomized to receive atorvastatin 20 mg (n = 11) or atorvastatin 5 mg/ezetimibe 10 mg combination (n = 10) for 8 weeks. The cholesterol efflux capacity and other anti-inflammatory functions were assessed based on HDLs of the participants before and after treatment. Pre-specified HDL proteins of the same HDL samples were measured.

Results: The post-treatment increase in cholesterol efflux capacities was similar between the groups (35.6% and 34.6% for mono-therapy and combination, respectively, p = 0.60). Changes in nitric oxide (NO) production, vascular cell adhesion molecule-1 (VCAM-1) expression, and reactive oxygen species (ROS) production were similar between the groups. The baseline cholesterol efflux capacity correlated positively with apolipoprotein (apo)A1 and C3, whereas apoA1 and apoC1 showed inverse associations with VCAM-1 expression. The changes in the cholesterol efflux capacity were positively correlated with multiple HDL proteins, especially apoA2.

Conclusions: Two regimens increased the cholesterol efflux capacity of HDL comparably. Multiple HDL proteins, not limited to apoA1, showed a correlation with HDL functions. These results indicate that conventional lipid therapy may have additional effects on HDL functions with changes in HDL proteins.

Trial registration: ClinicalTrials.gov, number NCT02942602 .

Keywords: Atorvastatin calcium; Cholesterol-efflux regulatory protein; Ezetimibe; Inflammation.

Figures

Fig. 1
Fig. 1
The parameters of high-density lipoprotein (HDL) function and the percentage changes after drug treatment. a and b) Cholesterol efflux capacity, c and d nitric oxide (NO) production, e and f vascular cell adhesion molecule-1 (VCAM-1) expression, and g and h reactive oxygen species (ROS) production

References

    1. Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371:2383–2393. doi: 10.1056/NEJMoa1409065.
    1. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–1681. doi: 10.1016/S0140-6736(10)61350-5.
    1. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Eur Heart J. 2011;32:1769–1818. doi: 10.1093/eurheartj/ehr158.
    1. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1–S45. doi: 10.1161/01.cir.0000437738.63853.7a.
    1. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372:2387–2397. doi: 10.1056/NEJMoa1410489.
    1. Shah AS, Tan L, Long JL, Davidson WS. Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond. J Lipid Res. 2013;54:2575–2585. doi: 10.1194/jlr.R035725.
    1. Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest. 2007;117:746–756. doi: 10.1172/JCI26206.
    1. Riwanto M, Rohrer L, Roschitzki B, Besler C, Mocharla P, Mueller M, et al. Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation. 2013;127:891–904. doi: 10.1161/CIRCULATIONAHA.112.108753.
    1. Huang Y, DiDonato JA, Levison BS, Schmitt D, Li L, Wu Y, et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med. 2014;20:193–203. doi: 10.1038/nm.3459.
    1. Green PS, Vaisar T, Pennathur S, Kulstad JJ, Moore AB, Marcovina S, et al. Combined statin and niacin therapy remodels the high-density lipoprotein proteome. Circulation. 2008;118:1259–1267. doi: 10.1161/CIRCULATIONAHA.108.770669.
    1. Miyamoto-Sasaki M, Yasuda T, Monguchi T, Nakajima H, Mori K, Toh R, et al. Pitavastatin increases HDL particles functionally preserved with cholesterol efflux capacity and antioxidative actions in dyslipidemic patients. J Atheroscler Thromb. 2013;20:708–716. doi: 10.5551/jat.17210.
    1. Gordon SM, McKenzie B, Kemeh G, Sampson M, Perl S, Young NS, et al. Rosuvastatin Alters the Proteome of High Density Lipoproteins: Generation of alpha-1-antitrypsin Enriched Particles with Anti-inflammatory Properties. Mol Cell Proteomics. 2015;14:3247–3257. doi: 10.1074/mcp.M115.054031.
    1. Her AY, Kim JY, Kang SM, Choi D, Jang Y, Chung N, et al. Effects of atorvastatin 20 mg, rosuvastatin 10 mg, and atorvastatin/ezetimibe 5 mg/5 mg on lipoproteins and glucose metabolism. J Cardiovasc Pharmacol Ther. 2010;15:167–174. doi: 10.1177/1074248409357922.
    1. Lee SH, Kang SM, Park S, Jang Y, Chung N, Choi D. The effects of statin monotherapy and low-dose statin/ezetimibe on lipoprotein-associated phospholipase A(2) Clin Cardiol. 2011;34:108–112. doi: 10.1002/clc.20853.
    1. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127–135. doi: 10.1056/NEJMoa1001689.
    1. Hermenegildo C, Medina P, Peiró M, Segarra G, Vila JM, Ortega J, et al. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in hyperthyroid patients. J Clin Endocrinol Metab. 2002;87:5636–5640. doi: 10.1210/jc.2002-020905.
    1. Seto SW, Krishna SM, Yu H, Liu D, Khosla S, Golledge J. Impaired acetylcholine-induced endothelium-dependent aortic relaxation by caveolin-1 in angiotensin II-infused apolipoprotein-E (ApoE-/-) knockout mice. PLoS ONE. 2013;8:e58481. doi: 10.1371/journal.pone.0058481.
    1. Speer T, Rohrer L, Blyszczuk P, Shroff R, Kuschnerus K, Kränkel N, et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity. 2013;38:754–768. doi: 10.1016/j.immuni.2013.02.009.
    1. Shroff R, Speer T, Colin S, Charakida M, Zewinger S, Staels B, et al. HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype. J Am Soc Nephrol. 2014;25:2658–2668. doi: 10.1681/ASN.2013111212.
    1. Zheng Z, Chen H, Ke G, Fan Y, Zou H, Sun X, et al. Protective effect of perindopril on diabetic retinopathy is associated with decreased vascular endothelial growth factor-to-pigment epithelium-derived factor ratio: involvement of a mitochondria-reactive oxygen species pathway. Diabetes. 2009;58:954–964. doi: 10.2337/db07-1524.
    1. Zhang Y, Liu J, Luo JY, Tian XY, Cheang WS, Xu J, et al. Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes. Antioxid Redox Signal. 2015;23:880–892. doi: 10.1089/ars.2014.6070.
    1. Cheon DH, Nam EJ, Park KH, Woo SJ, Lee HJ, Kim HC, et al. Comprehensive Analysis of Low-Molecular-Weight Human Plasma Proteome Using Top-Down Mass Spectrometry. J Proteome Res. 2016;15:229–244. doi: 10.1021/acs.jproteome.5b00773.
    1. Triolo M, Annema W, de Boer JF, Tietge UJ, Dullaart RP. Simvastatin and bezafibrate increase cholesterol efflux in men with type 2 diabetes. Eur J Clin Invest. 2014;44:240–248. doi: 10.1111/eci.12226.
    1. Shimizu T, Miura S, Tanigawa H, Kuwano T, Zhang B, Uehara Y, et al. Rosuvastatin activates ATP-binding cassette transporter A1-dependent efflux ex vivo and promotes reverse cholesterol transport in macrophage cells in mice fed a high-fat diet. Arterioscler Thromb Vasc Biol. 2014;34:2246–2253. doi: 10.1161/ATVBAHA.114.303715.
    1. Nicholls SJ, Ruotolo G, Brewer HB, Kane JP, Wang MD, Krueger KA, et al. Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated With Evacetrapib. J Am Coll Cardiol. 2015;66:2201–2210. doi: 10.1016/j.jacc.2015.09.013.
    1. Davidson MH, Voogt J, Luchoomun J, Decaris J, Killion S, Boban D, et al. Inhibition of intestinal cholesterol absorption with ezetimibe increases components of reverse cholesterol transport in humans. Atherosclerosis. 2013;230:322–329. doi: 10.1016/j.atherosclerosis.2013.08.006.
    1. Uto-Kondo H, Ayaori M, Sotherden GM, Nakaya K, Sasaki M, Yogo M, et al. Ezetimibe enhances macrophage reverse cholesterol transport in hamsters: contribution of hepato-biliary pathway. Biochim Biophys Acta. 1841;2014:1247–1255.
    1. Aharoni S, Aviram M, Fuhrman B. Paraoxonase 1 (PON1) reduces macrophage inflammatory responses. Atherosclerosis. 2013;228:353–361. doi: 10.1016/j.atherosclerosis.2013.03.005.
    1. Huang Y, Wu Z, Riwanto M, Gao S, Levison BS, Gu X, et al. Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex. J Clin Invest. 2013;123:3815–3828. doi: 10.1172/JCI67478.
    1. Johnson WJ, Mahlberg FH, Rothblat GH, Phillips MC. Cholesterol transport between cells and high-density lipoproteins. Biochim Biophys Acta. 1991;1085:273–298. doi: 10.1016/0005-2760(91)90132-2.
    1. Calabresi L, Franceschini G, Sirtori CR, De Palma A, Saresella M, Ferrante P, et al. Inhibition of VCAM-1 expression in endothelial cells by reconstituted high density lipoproteins. Biochem Biophys Res Commun. 1997;238:61–65. doi: 10.1006/bbrc.1997.7236.
    1. Cheung MC, Mendez AJ, Wolf AC, Knopp RH. Characterization of apolipoprotein A-I- and A-II-containing lipoproteins in a new case of high density lipoprotein deficiency resembling Tangier disease and their effects on intracellular cholesterol efflux. J Clin Invest. 1993;91:522–529. doi: 10.1172/JCI116231.
    1. Hara H, Yokoyama S. Interaction of free apolipoproteins with macrophages. Formation of high density lipoprotein-like lipoproteins and reduction of cellular cholesterol. J Biol Chem. 1991;266:3080–3086.
    1. Remaley AT, Stonik JA, Demosky SJ, Neufeld EB, Bocharov AV, Vishnyakova TG, et al. Apolipoprotein specificity for lipid efflux by the human ABCAI transporter. Biochem Biophys Res Commun. 2001;280:818–823. doi: 10.1006/bbrc.2000.4219.
    1. Sankaranarayanan S, Oram JF, Asztalos BF, Vaughan AM, Lund-Katz S, Adorni MP, et al. Effects of acceptor composition and mechanism of ABCG1-mediated cellular free cholesterol efflux. J Lipid Res. 2009;50:275–284. doi: 10.1194/jlr.M800362-JLR200.
    1. Westerterp M, Berbee JF, Pires NM, van Mierlo GJ, Kleemann R, Romijn JA, et al. Apolipoprotein C-I is crucially involved in lipopolysaccharide-induced atherosclerosis development in apolipoprotein E-knockout mice. Circulation. 2007;116:2173–2181. doi: 10.1161/CIRCULATIONAHA.107.693382.
    1. Cudaback E, Li X, Yang Y, Yoo T, Montine KS, Craft S, et al. Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation. J Neuroinflammation. 2012;9:192. doi: 10.1186/1742-2094-9-192.
    1. Petropoulou PI, Berbee JF, Theodoropoulos V, Hatziri A, Stamou P, Karavia EA, et al. Lack of LCAT reduces the LPS-neutralizing capacity of HDL and enhances LPS-induced inflammation in mice. Biochim Biophys Acta. 1852;2015:2106–2115.
    1. Jong MC, Hofker MH, Havekes LM. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc Biol. 1999;19:472–484. doi: 10.1161/01.ATV.19.3.472.
    1. Pamir N, Hutchins P, Ronsein G, Vaisar T, Reardon CA, Getz GS, et al. Proteomic analysis of HDL from inbred mouse strains implicates APOE associated with HDL in reduced cholesterol efflux capacity via the ABCA1 pathway. J Lipid Res. 2016;57:246–257.

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