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Analysis of S100A12 plasma levels in hyperlipidemic subjects with or without familial hypercholesterolemia

Acta Diabetologica volume 56, pages 899–906 (2019)Cite this article

Abstract

Aims

Inflammation is a key regulatory process that links hypercholesterolemia and immune mechanisms promoting atherosclerosis. Inflammatory biomarkers may be helpful to better define the atherosclerotic burden in patients with high cholesterol levels such as familial hypercholesterolemia (FH). Our aim was to evaluate the concentration of S100A12 protein in FH patients and its association with pulse wave velocity (PWV).

Methods

We measured glucose and lipid profile, S100A12, sRAGE, esRAGE and PWV in 39 patients with a genetically confirmed diagnosis of FH and 39 hypercholesterolemic subjects without a clinical diagnosis of FH (Dutch score ≤ 3). All subjects were on statin treatment at the time of the enrollment.

Results

No difference of glucose and lipid profile was found in the two groups. FH patients had higher S100A12 plasma levels than non-FH subjects (12.87 ± 4.82 vs. 8.57 ± 4.87 ng/mL, p < 0.01). No difference of hs-CRP, sRAGE and esRAGE was found between the two groups. Also, PWV was higher in FH patients than non-FH subjects (8.63 ± 0.92 vs. 6.68 ± 0.73 m/s, p < 0.05). Finally, S100A12 was independently correlated with age (p < 0.01), genetic mutation (p < 0.01) and PWV (p < 0.001).

Conclusions

FH patients exhibited higher S100A12 levels than non-FH subjects. A novel vascular inflammation pathway, other than hs-CRP, might be useful to better characterize cardiovascular risk profile.

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References

  1. Havel RJ (1989) Biology of cholesterol, lipoproteins and atherosclerosis. Clin Exp Hypertens Part A Theory Pract 11:887–900. https://doi.org/10.3109/10641968909035380

    Article  CAS  Google Scholar 

  2. Borén J, Williams KJ (2016) The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity. Curr Opin Lipidol 27:473–483. https://doi.org/10.1097/MOL.0000000000000330

    Article  CAS  PubMed  Google Scholar 

  3. GBD 2013 Mortality and Causes of Death Collaborators (2015) Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet (London, England) 385:117–171. https://doi.org/10.1016/S0140-6736(14)61682-2

    Article  Google Scholar 

  4. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695. https://doi.org/10.1056/NEJMra043430

    Article  CAS  Google Scholar 

  5. Ridker PM, Everett BM, Thuren T et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131. https://doi.org/10.1056/NEJMoa1707914

    Article  CAS  Google Scholar 

  6. Hansson GK, Libby P (2006) The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 6:508–519. https://doi.org/10.1038/nri1882

    Article  CAS  PubMed  Google Scholar 

  7. van Dijk RA, Duinisveld AJF, Schaapherder AF et al (2015) A change in inflammatory footprint precedes plaque instability: a systematic evaluation of cellular aspects of the adaptive immune response in human atherosclerosis. J Am Heart Assoc 4:e001403. https://doi.org/10.1161/JAHA.114.001403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lebedeva A, Vorobyeva D, Vagida M et al (2017) Ex vivo culture of human atherosclerotic plaques: a model to study immune cells in atherogenesis. Atherosclerosis 267:90–98. https://doi.org/10.1016/j.atherosclerosis.2017.10.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pirillo A, Garlaschelli K, Arca M et al (2017) Spectrum of mutations in Italian patients with familial hypercholesterolemia: new results from the LIPIGEN study. Atheroscler Suppl 29:17–24. https://doi.org/10.1016/j.atherosclerosissup.2017.07.002

    Article  PubMed  Google Scholar 

  10. Averna M, Cefalù AB, Casula M et al (2017) Familial hypercholesterolemia: the Italian atherosclerosis society network (LIPIGEN). Atheroscler Suppl 29:11–16. https://doi.org/10.1016/j.atherosclerosissup.2017.07.001

    Article  PubMed  Google Scholar 

  11. Basta G (2008) Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications. Atherosclerosis 196:9–21. https://doi.org/10.1016/j.atherosclerosis.2007.07.025

    Article  CAS  PubMed  Google Scholar 

  12. Koyama H, Nishizawa Y (2010) AGEs/RAGE in CKD: irreversible metabolic memory road toward CVD? Eur J Clin Investig 40:623–635. https://doi.org/10.1111/j.1365-2362.2010.02298.x

    Article  CAS  Google Scholar 

  13. Hofmann MA, Drury S, Fu C et al (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97:889–901

    Article  CAS  PubMed  Google Scholar 

  14. Hofmann Bowman MA, Schmidt AM (2011) S100/calgranulins EN-RAGEing the blood vessels: implications for inflammatory responses and atherosclerosis. Am J Cardiovasc Dis 1:92–100

    CAS  PubMed  Google Scholar 

  15. Yang Z, Tao T, Raftery MJ et al (2001) Proinflammatory properties of the human S100 protein S100A12. J Leukoc Biol 69:986–994

    CAS  PubMed  Google Scholar 

  16. Kosaki A, Hasegawa T, Kimura T et al (2004) Increased plasma S100A12 (EN-RAGE) levels in patients with type 2 Diabetes. J Clin Endocrinol Metab 89:5423–5428. https://doi.org/10.1210/jc.2003-032223

    Article  CAS  PubMed  Google Scholar 

  17. Foell D, Kane D, Bresnihan B et al (2003) Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic arthritis. Rheumatology 42:1383–1389. https://doi.org/10.1093/rheumatology/keg385

    Article  CAS  PubMed  Google Scholar 

  18. Gawdzik J, Mathew L, Kim G et al (2011) Vascular remodeling and arterial calcification are directly mediated by S100A12 (EN-RAGE) in chronic kidney disease. Am J Nephrol 33:250–259. https://doi.org/10.1159/000324693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yonekura H, Yamamoto Y, Sakurai S et al (2003) Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J 370:1097–1109. https://doi.org/10.1042/BJ20021371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Di Pino A, Mangiafico S, Urbano F et al (2017) HbA < inf > 1c </inf > identifies subjects with prediabetes and subclinical left ventricular diastolic dysfunction. J Clin Endocrinol Metab. https://doi.org/10.1210/jc.2017-00954

    Article  PubMed  Google Scholar 

  21. Ikonomidis I, Makavos G, Lekakis J (2015) Arterial stiffness and coronary artery disease. Curr Opin Cardiol 30:1. https://doi.org/10.1097/HCO.0000000000000179

    Article  Google Scholar 

  22. Scicali R, Di Pino A, Platania R et al (2018) Detecting familial hypercholesterolemia by serum lipid profile screening in a hospital setting: Clinical, genetic and atherosclerotic burden profile. Nutr Metab Cardiovasc Dis. https://doi.org/10.1016/j.numecd.2017.07.003

    Article  PubMed  Google Scholar 

  23. Nordestgaard BG, Chapman MJ, Humphries SE et al (2013) Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 34:3478–90a. https://doi.org/10.1093/eurheartj/eht273

    Article  CAS  PubMed  Google Scholar 

  24. Stone NJ, Robinson JG, Lichtenstein AH et al (2014) 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol 63:2889–2934. https://doi.org/10.1016/j.jacc.2013.11.002

    Article  Google Scholar 

  25. Ryan H, Trosclair A, Gfroerer J (2012) Adult current smoking: differences in definitions and prevalence estimates—NHIS and NSDUH, 2008. J Environ Public Health 2012:918368. https://doi.org/10.1155/2012/918368

    Article  PubMed  PubMed Central  Google Scholar 

  26. International Federation of Clinical Chemistry and Laboratory Medicine, IFCC Scientific Division IF of C, Mosca A, Goodall I et al (2007) Global standardization of glycated hemoglobin measurement: the position of the IFCC working group. Clin Chem Lab Med 45:1077–1080. https://doi.org/10.1515/CCLM.2007.246

    Article  CAS  Google Scholar 

  27. Di Pino A, Currenti W, Urbano F et al (2017) High intake of dietary advanced glycation end-products is associated with increased arterial stiffness and inflammation in subjects with type 2 diabetes. Nutr Metab Cardiovasc Dis. https://doi.org/10.1016/j.numecd.2017.06.014

    Article  PubMed  Google Scholar 

  28. Mori Y, Kosaki A, Kishimoto N et al (2009) Increased plasma S100A12 (EN-RAGE) levels in hemodialysis patients with atherosclerosis. Am J Nephrol 29:18–24. https://doi.org/10.1159/000148646

    Article  CAS  PubMed  Google Scholar 

  29. Di Pino A, Urbano F, Zagami RM et al (2016) Low endogenous secretory receptor for advanced glycation end-products levels are associated with inflammation and carotid atherosclerosis in prediabetes. J Clin Endocrinol Metab 101:1701–1709. https://doi.org/10.1210/jc.2015-4069

    Article  CAS  PubMed  Google Scholar 

  30. Scicali R, Giral P, Gallo A et al (2016) HbA1c increase is associated with higher coronary and peripheral atherosclerotic burden in non diabetic patients. Atherosclerosis 255:102–108. https://doi.org/10.1016/j.atherosclerosis.2016.11.003

    Article  CAS  PubMed  Google Scholar 

  31. Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126. https://doi.org/10.1056/NEJM199901143400207

    Article  CAS  Google Scholar 

  32. Menini S, Iacobini C, Ricci C et al (2013) The galectin-3/RAGE dyad modulates vascular osteogenesis in atherosclerosis. Cardiovasc Res 100:472–480. https://doi.org/10.1093/cvr/cvt206

    Article  CAS  PubMed  Google Scholar 

  33. Mollazadeh H, Carbone F, Montecucco F et al (2018) Oxidative burden in familial hypercholesterolemia. J Cell Physiol. https://doi.org/10.1002/jcp.26466

    Article  PubMed  Google Scholar 

  34. Scicali R, Di Pino A, Ferrara V et al (2018) New treatment options for lipid-lowering therapy in subjects with type 2 diabetes. Acta Diabetol. https://doi.org/10.1007/s00592-017-1089-4

    Article  PubMed  Google Scholar 

  35. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG (2012) Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab 97:3956–3964. https://doi.org/10.1210/jc.2012-1563

    Article  CAS  PubMed  Google Scholar 

  36. Ligthart S, Sedaghat S, Ikram MA et al (2014) EN-RAGE: a novel inflammatory marker for incident coronary heart disease. Arterioscler Thromb Vasc Biol 34:2695–2699. https://doi.org/10.1161/ATVBAHA.114.304306

    Article  CAS  PubMed  Google Scholar 

  37. Nowak C, Carlsson AC, Östgren CJ et al (2018) Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes. Diabetologia 61:1748–1757. https://doi.org/10.1007/s00125-018-4641-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Di Pino A, Scicali R, Calanna S et al (2014) Cardiovascular risk profile in subjects with prediabetes and new-onset type 2 diabetes identified by HbA1c according to american diabetes association criteria. Diabetes Care 37:1447–1453. https://doi.org/10.2337/dc13-2357

    Article  CAS  PubMed  Google Scholar 

  39. Quade-Lyssy P, Kanarek AM, Baiersdörfer M et al (2013) Statins stimulate the production of a soluble form of the receptor for advanced glycation end products. J Lipid Res 54:3052–3061. https://doi.org/10.1194/jlr.M038968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ridker PM, Danielson E, Fonseca FA et al (2009) Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet (London, England) 373:1175–1182. https://doi.org/10.1016/S0140-6736(09)60447-5

    Article  CAS  Google Scholar 

  41. Scicali R, Rosenbaum D, Di Pino A et al (2018) An increased waist-to-hip ratio is a key determinant of atherosclerotic burden in overweight subjects. Acta Diabetol. https://doi.org/10.1007/s00592-018-1144-9

    Article  PubMed  Google Scholar 

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Acknowledgements

F.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version. The authors wish to thank the Department of Clinical and Experimental Medicine for financial support in the context of the 2016/2018 Department Research Plan of University of Catania (Project #A). The authors wish to thank the Lipid TransPort Disorders Italian Genetic Network (LIPIGEN) study for financial support to carry out genetic analysis. The authors wish to thank the Scientific Bureau of the University of Catania for language support.

Funding

This research did not receive any specific grant from funding agencies in the commercial or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi Hospital, University of Catania, Via Palermo, 636 95122, Catania, Italy

    Roberto Scicali, Antonino Di Pino, Francesca Urbano, Viviana Ferrara, Simona Marchisello, Stefania Di Mauro, Alessandra Scamporrino, Agnese Filippello, Salvatore Piro, Agata Maria Rabuazzo & Francesco Purrello

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  1. Roberto Scicali
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Contributions

RS contributed to the study design, researched data, contributed to the discussion, and wrote the article. ADP contributed to the study design, researched data, contributed to the discussion, and reviewed and edited the article. FU, VF, SDM, SM, AS, AF, researched data, contributed to the discussion, and reviewed and edited the article. SP and AMR contributed to the study design and discussion, and reviewed and edited the article. FP designed the study, researched data, contributed to the discussion, and reviewed and edited the article.

Corresponding author

Correspondence to Francesco Purrello.

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The authors have no conflicts of interest to disclose.

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This study has been approved by the local ethic committee in accordance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from each participants included in the study.

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Scicali, R., Di Pino, A., Urbano, F. et al. Analysis of S100A12 plasma levels in hyperlipidemic subjects with or without familial hypercholesterolemia. Acta Diabetol 56, 899–906 (2019). https://doi.org/10.1007/s00592-019-01338-1

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Keywords

  • Familial hypercholesterolemia
  • S100A12
  • Inflammation
  • Pulse wave velocity
  • Cardiovascular risk