Download PDF
Thromb Haemost 2015; 113(06): 1335-1346
DOI: 10.1160/TH14-10-0874
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

ApoA-I/HDL-C levels are inversely associated with abdominal aortic aneurysm progression

Elena Burillo   *
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Jes S. Lindholt   *
2   Departments of Cardiovascular and Thoracic Surgery, University Hospitals of Odense, Viborg and Aarhus, Denmark
,
Pedro Molina-Sánchez
3   Molecular and Genetic Cardiovascular Pathophysiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
,
Inmaculada Jorge
4   Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
,
Roxana Martinez-Pinna
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Luis Miguel Blanco-Colio
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Carlos Tarin
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Monica Maria Torres-Fonseca
2   Departments of Cardiovascular and Thoracic Surgery, University Hospitals of Odense, Viborg and Aarhus, Denmark
,
Margarita Esteban
5   Hospital de Cruces, Vizcaya, Spain
,
Jesper Laustsen
2   Departments of Cardiovascular and Thoracic Surgery, University Hospitals of Odense, Viborg and Aarhus, Denmark
,
Priscila Ramos-Mozo
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Enrique Calvo
4   Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
,
Juan Antonio Lopez
4   Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
,
Melina Vega de Ceniga
6   Hospital de Galdakao, Vizcaya, Spain
,
Jean-Baptiste Michel
7   Inserm, U1148, Univ Paris 7, CHU X-Bichat, Paris, France
,
Jesus Egido
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
8   Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
,
Vicente Andrés
3   Molecular and Genetic Cardiovascular Pathophysiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
,
Jesús Vazquéz
4   Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
,
Olivier Meilhac
2   Departments of Cardiovascular and Thoracic Surgery, University Hospitals of Odense, Viborg and Aarhus, Denmark
9   CHU de La Réunion, Saint-Denis, France
,
Jose Luis Martin-Ventura
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
› Author Affiliations Financial support: Financial support for the study was provided by the 7th European framework programme: Health-2007–2.4.2–2; project title: Fighting Aneurysmal Disease, the Spanish MINECO (SAF2013/42525), Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Redes RIC (RD12/0042/0056, RD12/0042/00038 and RD12/0042/0028), biobancos (RD09/0076/00101), PI10/00072, PI14/00386, PIE13/00051 and FRIAT. P.M-S. is supported by a FPU predoctoral fellowship from the Spanish MINECO. OM was supported by ANR JCJC1105. CNIC is supported by the MINECO and the Pro-CNIC Foundation.
Further Information

Publication History

Received: 22 October 2014

Accepted after major revision: 21 January 2015

Publication Date:
29 November 2017 (online)

    Permissions and Reprints

Summary

Abdominal aortic aneurysm (AAA) evolution is unpredictable, and there is no therapy except surgery for patients with an aortic size > 5 cm (large AAA). We aimed to identify new potential biomarkers that could facilitate prognosis and treatment of patients with AAA. A differential quantitative proteomic analysis of plasma proteins was performed in AAA patients at different stages of evolution [small AAA (aortic size=3�5cm) vs large AAA] using iTRAQ labelling, highthroughput nano-LC-MS/MS and a novel multi-layered statistical model. Among the proteins identified, ApoA-I was decreased in patients with large AAA compared to those with small AAA. These results were validated by ELISA on plasma samples from small (n=90) and large AAA (n=26) patients (150 ± 3 vs 133 ± 5 mg/dl, respectively, p< 0.001). ApoA-I levels strongly correlated with HDL-Cholesterol (HDL-C) concentration (r=0.9, p< 0.001) and showed a negative correlation with aortic size (r=-0.4, p< 0.01) and thrombus volume (r=-0.3, p< 0.01), which remained significant after adjusting for traditional risk factors. In a prospective study, HDL-C independently predicted aneurysmal growth rate in multiple linear regression analysis (n=122, p=0.008) and was inversely associated with need for surgical repair (Adjusted hazard ratio: 0.18, 95 % confidence interval: 0.04�0.74, p=0.018). In a nation-wide Danish registry, we found lower mean HDL-C concentration in large AAA patients (n=6,560) compared with patients with aorto-iliac occlusive disease (n=23,496) (0.89 ± 2.99 vs 1.59 ± 5.74 mmol/l, p< 0.001). Finally, reduced mean aortic AAA diameter was observed in AngII-infused mice treated with ApoA-I mimetic peptide compared with saline-injected controls. In conclusion, ApoAI/ HDL-C systemic levels are negatively associated with AAA evolution. Therapies targeting HDL functionality could halt AAA formation.

Keywords

Vascular remodelling - lipoproteins - proteomics - abdominal aortic aneurysm

* Equal contribution of first authors.


 

  • References

  • 1 Sakalihasan N, Limet R. Defawe OD. Abdominal aortic aneurysm Lancet 2005; 365: 1577-1589.
    CrossrefPubMedGoogle Scholar
  • 2 Limet R, Sakalihassan N, Albert A. Determination of the expansion rate and incidence of rupture of abdominal aortic aneurysms. J Vasc Surg 1991; 14: 540-548.
    CrossrefPubMedGoogle Scholar
  • 3 Pernemalm M, Lewensohn R, Lehtiö J. Affinity prefractionation for MS-based plasma proteomics. Proteomics 2009; 09: 1420-1427.
    CrossrefPubMedGoogle Scholar
  • 4 Lei T, He QY, Wang YL. et al. Heparin chromatography to deplete high-abundance proteins for serum proteomics. Clin Chim Acta 2008; 388: 173-178.
    CrossrefPubMedGoogle Scholar
  • 5 Gamberi T, Puglia M, Guidi F. et al. A proteomic approach to identify plasma proteins in patients with abdominal aortic aneurysm. Mol Biosyst 2011; 07: 2855-2862.
    CrossrefPubMedGoogle Scholar
  • 6 Acosta-Martin AE, Panchaud A, Chwastyniak M. et al. Quantitative mass spectrometry analysis using PAcIFIC for the identification of plasma diagnostic biomarkers for abdominal aortic aneurysm. PLoS One 2011; 06: e28698.
    CrossrefPubMedGoogle Scholar
  • 7 Wallinder J, Bergström J, Henriksson AE. Discovery of a novel circulating biomarker in patients with abdominal aortic aneurysm: a pilot study using a proteomic approach. Clin Transl Sci 2012; 05: 56-59.
    CrossrefPubMedGoogle Scholar
  • 8 Spadaccio C, Di Domenico F, Perluigi M. et al. Serum proteomics in patients with diagnosis of abdominal aortic aneurysm. Cardiovasc Pathol. 2012; 21: 283-290.
    PubMedGoogle Scholar
  • 9 Martinez-Pinna R, Lindholt JS, Madrigal-Matute J. et al. From tissue iron retention to low systemic haemoglobin levels, new pathophysiological biomarkers of human abdominal aortic aneurysm. Thromb Haemost 2014; 112: 87-95.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 O’Brien KD, Pineda C, Chiu WS. et al. Glycosylphosphatidylinositol-specific phospholipase D is expressed by macrophages in human atherosclerosis and colocalizes with oxidation epitopes. Circulation 1999; 99: 2876-2882.
    CrossrefPubMedGoogle Scholar
  • 11 Martínez-Bartolomé S, Navarro P, Martín-Maroto F. et al. Properties of average score distributions of SEQUEST: the probability ratio method. Mol Cell Proteomics 2008; 07: 1135-1145.
    CrossrefPubMedGoogle Scholar
  • 12 Navarro P, Vázquez J. A refined method to calculate false discovery rates for peptide identification using decoy databases. J Proteome Res 2009; 08: 1792-1796.
    CrossrefPubMedGoogle Scholar
  • 13 Jorge I, Navarro P, Martínez-Acedo P. et al. Statistical model to analyse quantitative proteomics data obtained by 18O/16O labelling and linear ion trap mass spectrometry: application to the study of vascular endothelial growth factor-induced angiogenesis in endothelial cells. Mol Cell Proteomics 2009; 08: 1130-1149.
    CrossrefPubMedGoogle Scholar
  • 14 Bonzon-Kulichenko E, Perez-Hernandez D, Nunez E. et al. A robust method for quantitative high-throughput analysis of proteomes by 18O labelling. Mol Cell Proteomics 2011; 10 M110 003335.
    PubMedGoogle Scholar
  • 15 Lindholt JS, Juul S, Fasting H. et al. Screening for abdominal aortic aneurysms: single centre randomised controlled trial. Br Med J 2005; 330: 750.
    CrossrefPubMedGoogle Scholar
  • 16 Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest 2000; 105: 1605-1612.
    CrossrefPubMedGoogle Scholar
  • 17 Navab M, Reddy ST, Anantharamaiah GM. et al. Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally. J Lipid Res 2011; 52: 1200-1210.
    CrossrefPubMedGoogle Scholar
  • 18 Datta G, Chaddha M, Hama S. et al. Effects of increasing hydrophobicity on the physical-chemical and biological properties of a class A amphipathic helical peptide. J Lipid Res 2001; 42: 1096-1104.
    PubMedGoogle Scholar
  • 19 Martin-McNulty B, Vincelette J, Vergona R. et al. Noninvasive measurement of abdominal aortic aneurysms in intact mice by a high-frequency ultrasound imaging system. Ultrasound Med Biol 2005; 31: 745-749.
    CrossrefPubMedGoogle Scholar
  • 20 Navarro P, Trevisan-Herraz M, Bonzon-Kulichenko E. et al. General statistical framework for quantitative proteomics by stable isotope labelling. J Proteome Res 2014; 13: 1234-1247.
    CrossrefPubMedGoogle Scholar
  • 21 Jorge I, Burillo E, Mesa R. et al. The human HDL proteome displays high interindividual variability and is altered dynamically in response to angioplasty-induced atheroma plaque rupture. J Proteomics 2014; 106: 61-73.
    CrossrefPubMedGoogle Scholar
  • 22 Green PH, Glickman RM, Riley JW. et al. Human apolipoprotein A-IV. Intestinal origin and distribution in plasma. J Clin Invest 1980; 65: 911-919.
    CrossrefPubMedGoogle Scholar
  • 23 Ahnström J, Gottsäter A, Lindblad B. et al. Plasma concentrations of apolipoproteins A-I, B and M in patients with abdominal aortic aneurysms. Clin Biochem 2010; 43: 407-410.
    CrossrefPubMedGoogle Scholar
  • 24 Golledge J, van Bockxmeer F, Jamrozik K. et al. Association between serum lipoproteins and abdominal aortic aneurysm. Am J Cardiol 2010; 105: 1480-1484.
    CrossrefPubMedGoogle Scholar
  • 25 Hellenthal FA, Pulinx B, Welten RJ. et al. Circulating biomarkers and abdominal aortic aneurysm size. J Surg Res 2012; 176: 672-678.
    CrossrefPubMedGoogle Scholar
  • 26 Martinez-Pinna R, Madrigal-Matute J, Tarin C. et al. Proteomic analysis of intraluminal thrombus highlights complement activation in human abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2013; 33: 2013-2020.
    CrossrefPubMedGoogle Scholar
  • 27 Mineo C, Shaul PW. Regulation of signal transduction by HDL. J Lipid Res 2013; 54: 2315-2324.
    CrossrefPubMedGoogle Scholar
  • 28 Wang P, Wang Y, Ma W. et al. High-density lipoprotein cholesterol and intracoronary thrombosis burden. Coron Artery Dis 2013; 24: 1-5.
    CrossrefPubMedGoogle Scholar
  • 29 Ramella NA, Rimoldi OJ, Prieto ED. et al. Human apolipoprotein A-I-derived amyloid: its association with atherosclerosis. PLoS One 2011; 06: e22532.
    CrossrefPubMedGoogle Scholar
  • 30 Mucchiano GI, Häggqvist B, Sletten K. et al. Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta. J Pathol 2001; 193: 270-275.
    CrossrefPubMedGoogle Scholar
  • 31 Mucchiano GI, Jonasson L, Häggqvist B. et al. Apolipoprotein A-I-derived amyloid in atherosclerosis. Its association with plasma levels of apolipoprotein A-I and cholesterol. Am J Clin Pathol 2001; 115: 298-303.
    CrossrefPubMedGoogle Scholar
  • 32 DiDonato JA, Huang Y, Aulak KS. et al. Function and distribution of apolipoprotein A1 in the artery wall are markedly distinct from those in plasma. Circulation 2013; 128: 1644-1655.
    CrossrefPubMedGoogle Scholar
  • 33 Lee-Rueckert M, Kovanen PT. Extracellular modifications of HDL in vivo and the emerging concept of proteolytic inactivation of preβ-HDL. Curr Opin Lipidol 2011; 22: 394-402.
    CrossrefPubMedGoogle Scholar
  • 34 Smith JD. Dysfunctional HDL as a diagnostic and therapeutic target. Arterioscler Thromb Vasc Biol 2010; 30: 151-155.
    CrossrefPubMedGoogle Scholar
  • 35 Holy EW, Besler C, Reiner MF. et al. High-density lipoprotein from patients with coronary heart disease loses anti-thrombotic effects on endothelial cells: impact on arterial thrombus formation. Thromb Haemost 2014; 112: 1024-1035.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Vaisar T, Pennathur S, Green PS. et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 2007; 117: 746-756.
    CrossrefPubMedGoogle Scholar
  • 37 Ortiz-Muñoz G, Houard X, Martín-Ventura JL. et al. HDL antielastase activity prevents smooth muscle cell anoikis, a potential new antiatherogenic property. FASEB J 2009; 23: 3129-3139.
    CrossrefPubMedGoogle Scholar
  • 38 Delbosc S, Diallo D, Dejouvencel T. et al. Impaired high-density lipoprotein anti-oxidant capacity in human abdominal aortic aneurysm. Cardiovasc Res 2013; 100: 307-315.
    CrossrefPubMedGoogle Scholar
  • 39 Tran-Dinh A, Diallo D, Delbosc S. et al. HDL and endothelial protection. Br J Pharmacol 2013; 169: 493-511.
    CrossrefPubMedGoogle Scholar
  • 40 Reddy ST, Wadleigh DJ, Grijalva V. et al. Human paraoxonase-3 is an HDL-associated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids. Arterioscler Thromb Vasc Biol 2001; 21: 542-547.
    CrossrefPubMedGoogle Scholar
  • 41 Garner B, Waldeck AR, Witting PK. et al. Oxidation of high density lipoproteins. II. Evidence for direct reduction of lipid hydroperoxides by methionine residues of apolipoproteins AI and AII. J Biol Chem 1998; 273: 6088-6095.
    CrossrefPubMedGoogle Scholar
  • 42 Murphy AJ, Woollard KJ, Hoang A. et al. High-density lipoprotein reduces the human monocyte inflammatory response. Arterioscler Thromb Vasc Biol 2008; 28: 2071-2077.
    CrossrefPubMedGoogle Scholar
  • 43 Krishna SM, Seto SW, Moxon JV. et al. Fenofibrate increases high-density lipoprotein and sphingosine 1 phosphate concentrations limiting abdominal aortic aneurysm progression in a mouse model. Am J Pathol 2012; 181: 706-718.
    CrossrefPubMedGoogle Scholar
  • 44 Torsney E, Pirianov G, Charolidi N. et al. Elevation of plasma high-density lipoproteins inhibits development of experimental abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2012; 32: 2678-2686.
    CrossrefPubMedGoogle Scholar
  • 45 Nissen S, Tsunoda T, Tuzcu E. et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. J Am Med Assoc 2003; 290: 2292-2300.
    CrossrefPubMedGoogle Scholar
  • 46 Morgantini C, Natali A, Boldrini B. et al. Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes. Diabetes 2011; 60: 2617-2623.
    CrossrefPubMedGoogle Scholar
  • 47 Gomaraschi M, Calabresi L, Rossoni G. et al. Anti-inflammatory and cardioprotective activities of synthetic high-density lipoprotein containing apolipoprotein A-I mimetic peptides. J Pharmacol Exp Ther 2008; 324: 776-783.
    PubMedGoogle Scholar
  • 48 Osei-Hwedieh DO, Amar M, Sviridov D. et al. Apolipoprotein mimetic peptides: Mechanisms of action as anti-atherogenic agents. Pharmacol Ther 2011; 130: 83-91.
    CrossrefPubMedGoogle Scholar
  • 49 Bloedon LT, Dunbar R, Duffy D. et al. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J Lipid Res 2008; 49: 1344-1352.
    CrossrefPubMedGoogle Scholar
  • 50 Laustsen J, Jensen LP, Hansen AK. et al. Accuracy of clinical data in a population based vascular registry. Eur J Vasc Endovasc Surg 2004; 27: 216-219.
    CrossrefPubMedGoogle Scholar
  • 51 Lindholt JS, Vammen S, Juul S. et al. The validity of ultrasonographic scanning as screening method for abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 1999; 17: 472-475.
    CrossrefPubMedGoogle Scholar