High serum S100A8/A9 levels and high cardiovascular complication rate in type 2 diabetics with ultrasonographic low carotid plaque density

https://doi.org/10.1016/j.diabres.2012.01.026Get rights and content

Abstract

Aims

S100A8/A9 complex is an inflammation-associated biomarker, which binds toll-like receptor 4 and was associated with the receptor for advanced glycation end-products. S100A8 and S100A9 were accumulated in atherosclerotic lesions. High serum levels of S100A8/A9 are associated with acute coronary syndrome and atherosclerosis in type 2 diabetes mellitus (T2DM). However, association between serum S100A8/A9 levels and vulnerable plaque remains unclear. The present study investigated the relation between serum S100A8/A9 levels and relative plaque density (RPD) of the carotid artery determined by ultrasonography in T2DM.

Methods

The study subjects were 72 consecutive T2DM outpatients (males/females = 42/30), who underwent the carotid artery ultrasonography. RPD in the carotid artery was calculated by the formula; RPD = [density of the carotid plaque/density of vessel lumen]. Serum levels of adiponectin and S100A8/A9 were measured.

Results

The median RPD was 2.1. Patients with low RPD (≤2.1) were significantly more likely to have metabolic syndrome, nephropathy, coronary artery disease, and peripheral artery disease, and higher levels of S100A8/A9, S100A8/A9-to-adiponectin ratio, and uric acid, compared to those with high RPD (>2.1).

Conclusions

T2DM patients with low RPD had higher prevalence of metabolic syndrome, cardiovascular diseases and higher serum S100A8/A9 levels, compared to those with high RPD.

Introduction

Diabetes accelerates the natural course of atherosclerosis. Patients with type 2 diabetes mellitus (T2DM) are at high risk for atherosclerotic vascular disease and plaque formation including brain ischemia, stroke, coronary artery disease and peripheral artery disease [1]. Atherosclerosis is a progressive chronic disease characterized by endothelial dysfunction and its initiation, progression, and outcome correlate with immune system dysfunction and chronic inflammation [2]. Since inflammation is the initial event in plaque instability [3], biomarkers of inflammation may provide insight into the cellular processes linked to plaque instability [4]. The inflammation-associated biomarker, myeloid-related protein 8/14 (MRP8/14) complex, is a heterodimer of two calcium-binding proteins [5], also termed calcranulin A and B, or S100A8 (MRP-8) and S100A9 (MRP-14). High serum levels of S100A8/A9 are associated with inflammatory disorders, such as autoimmune disease [6], acute coronary syndrome [7], [8], [9], [10], [11] and atherosclerosis in T2DM [12] (vulnerable blood). S100A8 and S100A9 are mainly expressed in inflammatory cells [13], mainly in activated granulocytes and macrophages [14], and accumulated in inflammatory [15] or atherosclerotic lesions [8], [10], [16], [17] (vulnerable lesions). These proteins are reported to have several functions such as activating NADPH oxidase [18], [19], binding toll-like receptor 4 [20] and associated with the receptor for advanced glycation end-products [21], which are vital signaling pathways involved in the pathogenesis atherosclerosis in T2DM. However, association between serum S100A8/A9 levels and vulnerable plaque remains unclear.

The present study investigated the relation between serum S100A8/A9 levels and relative plaque density of the carotid artery determined by ultrasonography in type 2 diabetics.

Section snippets

Subjects

This study, an ongoing population-based study designed to investigate atherosclerosis development in metabolic syndrome – the ultrasound study (ADMIT study), is registered under number UMIN 000002271 [22] [http://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000002777&language=E]. The study subjects constituted a sample of Japanese with diabetes and/or metabolic syndrome who visit Osaka University Hospital. The Medical Ethics Committee of Osaka

Characteristics of patients

The baseline characteristics of the 72 T2DM patients with carotid plaque are listed in Table 1. In the present study, visceral fat accumulation (eVFA ≥100 cm2) was identified in 63% (n = 45/72) patients, based on the Japanese criteria of visceral fat accumulation [27]. Fig. 1B is a histogram of RPD values in the diabetic patients (range; 1.2–4.5). The median and mean RPD for the entire group were 2.1 and 2.4, respectively.

Clinical features according to the RPD value

Patients with T2DM were divided into two groups using a cutoff RPD value of

Discussion

The major findings of the present study were that T2DM patients in low RPD group were more likely to have the metabolic syndrome based on visceral fat accumulation, higher levels of S100A8/A9, S100A8/A9 to adiponectin ratio, uric acid, and higher prevalence of cardiovascular diseases, compared in those of the high RPD group. On the other hand, there was no significant difference of carotid IMTs (mean IMT and max IMT) in the two groups. The carotid IMTs, plaque scoring (size and counts) and

Conflict of interest

The authors declare that they have no conflict of interest. Ken Kishida and Tohru Funahashi are members of the “Department of Metabolism and Atherosclerosis”, a sponsored course endowed by Kowa Co. Ltd. and a company researcher is dispatched to the course.

Contributions

A.H. and K.K. recruited the patients, collected and analyzed the data, and wrote the manuscript. K.K. also participated in the concept and design of the study, interpretation of data and reviewed/edited the manuscript. A.H.-S. and H.N. recruited and examined the patients, and collected the data. T.F. and I.S. contributed to the discussion and wrote the manuscript. All authors read and approved the final version of the manuscript.

Acknowledgments

We thank all staff at “Diabetes & Metabolic Station” for the excellent medical care, Dr. Norikazu Maeda for patient enrolment, and Mrs Yoko Motomura and Miyuki Nakamura for the excellent technical assistance. This research was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area) “Molecular Basis and Disorders of Control of Appetite and Fat Accumulation” (#22126008, to T.F. and K.K., Chiyoda, Tokyo, Japan).

References (40)

  • K. Maeda et al.

    Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1)

    Biochem Biophys Res Commun

    (1996)
  • Y. Arita et al.

    Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity

    Biochem Biophys Res Commun

    (1999)
  • P. Libby et al.

    Stabilization of atherosclerotic plaques: new mechanisms and clinical targets

    Nat Med

    (2002)
  • G.K. Hansson

    Inflammation, atherosclerosis, and coronary artery disease

    N Engl J Med

    (2005)
  • R.S. Vasan

    Biomarkers of cardiovascular disease: molecular basis and practical considerations

    Circulation

    (2006)
  • M. Frosch et al.

    Myeloid-related proteins 8 and 14 are specifically secreted during interaction of phagocytes and activated endothelium and are useful markers for monitoring disease activity in pauciarticular-onset juvenile rheumatoid arthritis

    Arthritis Rheum

    (2000)
  • A.M. Healy et al.

    Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events

    Circulation

    (2006)
  • L.A. Altwegg et al.

    Myeloid-related protein 8/14 complex is released by monocytes and granulocytes at the site of coronary occlusion: a novel, early, and sensitive marker of acute coronary syndromes

    Eur Heart J

    (2007)
  • S. Miyamoto et al.

    Increased serum levels and expression of S100A8/A9 complex in infiltrated neutrophils in atherosclerotic plaque of unstable angina

    Heart

    (2008)
  • M.G. Ionita et al.

    High levels of myeloid-related protein 14 in human atherosclerotic plaques correlate with the characteristics of rupture-prone lesions

    Arterioscler Thromb Vasc Biol

    (2009)
  • Cited by (24)

    • S100 proteins in atherosclerosis

      2020, Clinica Chimica Acta
      Citation Excerpt :

      However, there were increasingly experimental data to prove that RAGE and TLR were closely related to the formation of atherosclerosis. As the ligands of RAGE and TLR-4, serum concentrations of S100A8, S100A9 and S100A12 are significantly elevated in acute coronary syndrome (ACS), coronary artery calcification, and cardiovascular intimal hyperplasia [12–14]. The binding of ligands including S100A8/A9 and S100A12 to RAGE could activate endothelial cells, vascular SMCs and inflammatory intracellular signal transduction pathways inducing transcription and secretion of pro-inflammatory cytokines and cell adhesion molecules, and leading to leukocyte infiltration, aggravation of oxidative stress and vascular inflammatory response [15].

    • S100 family proteins in inflammation and beyond

      2020, Advances in Clinical Chemistry
      Citation Excerpt :

      Increased serum S100A8/A9 are associated with ACS and atherosclerosis in T2DM. S100A8/A9 accumulates in atherosclerotic lesions and high serum S100A8/A9 is a marker for low carotid plaque density [447]. In patients with T2DM and nephropathy, S100A8/A9 is a marker for transendothelial migration of monocytes and neutrophils and microcirculatory complications independent of hypertension and dyslipidemia [448].

    • Effect of poly and mono-unsaturated fatty acids on stability and structure of recombinant S100A8/A9

      2016, International Journal of Biological Macromolecules
      Citation Excerpt :

      The fact that the individual components of the protein complex are unable to bind fatty acids in neither the absence nor the presence of calcium leads to the assumption that docking of the two subunits creates an asymmetric fatty acid-binding site located at the interface between the subunits [49]. Many studies have shown a significant increase in S100A8/A9 in atherosclerosis [24,50], demonstrating that S100A8/A9 complexes secreted by activated phagocytes bind specifically to endothelial cells and directly activated the microvascular endothelium. This leads to a loss of barrier function, apoptosis of endothelial cells, upregulation of thrombogenic factors and an increase in junctional permeability [6,51].

    • Role of calprotectin in cardiometabolic diseases

      2014, Cytokine and Growth Factor Reviews
      Citation Excerpt :

      The areas under the ROC curves for CAD were 0.63 (95% CI 0.57–0.68) for calprotectin, 0.76 (95% CI 0.71–0.81) for hsCRP and 0.62 (95% CI 0.56 –0.67) for esRAGE [77]. Levels of calprotectin further correlated with relative plaque density (RPD) of the carotid artery plaques determined by ultrasonography in T2DM patients in the study by Hirata et al. [78]: patients with low RPD (bellow the median, i.e. ≤2.1) were more likely to have metabolic syndrome, nephropathy, CAD, and peripheral artery disease, higher levels of calprotectin, calprotectin-to-adiponectin ratio, and uric acid, compared to those with RPD above the median (i.e. >2.1) [78]. Ionita et al. (2009) quantified levels of calprotectin and its subunits in 186 human carotid plaques [79].

    • Gene expression levels of S100 protein family in blood cells are associated with insulin resistance and inflammation (Peripheral blood S100 mRNAs and metabolic syndrome)

      2013, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      Our group for the first time demonstrated that S100A8 is highly expressed in obese adipose tissues and adipose S100A8 is significantly reduced by peroxisome proliferator-activated receptor-γ (PPARγ) agonist, indicating that S100A8 is one of adipocytokines [8]. Furthermore, we recently showed that circulating level of calprotectin (S100A8/A9 complex) is positively correlated with visceral fat area [9] and is associated with low ultrasonographic low carotid plaque density [10]. Several groups have also showed the clinical significance of calprotectin and suggested that calprotectin is a novel biomarker of cardiovascular events [11–13].

    View all citing articles on Scopus
    View full text