Opposite relationship between circulating soluble CD14 concentration and endothelial function in diabetic and nondiabetic subjects

Summary

Recent prospective studies indicate endothelial dysfunction and increased risk for cardiovascular events in patients with serological evidence of multiple infections. Soluble CD14 (sCD14) plays a key role in the neutralization of lipopolysaccharide (LPS), a well-established bacterial product inducing endothelial dysfunction. Insulin resistance was recently identified as a significant factor influencing circulating sCD14 concentration. Thus, we investigated the association of circulating sCD14 and endothelial dysfunction in subjects with well-established insulin resistance (patients with type 2 diabetes, n=40) compared to control nondiabetic subjects (n=100). To further explore the underlying mechanisms, we also analysed C-reactive protein and circulating NO2-/NO3- and cyclic GMP in the diabetic group. Serum sCD14 concentration (ELISA) was found to be differently associated with endothelium-dependent vasodilatation (EDVD, high-resolution ultrasound) in diabetic and non-diabetic subjects. In nondiabetic subjects, serum sCD14 and C-reactive protein correlated negatively with EDVD (r= −0.21, p=0.03, and r=−0.21, p=0.03, respectively). In a partial correlation analysis, these associations remained significant after controlling for age and weight (sCD14 and EDVD, r=−0.23, p=0.023; C-reactive protein and EDVD, r=−0.21, p=0.03; sCD14 and C-reactive protein, r=0.30, p=0.002). In contrast, sCD14 was positively associated with EDVD in type 2 diabetic patients (r= 0.37, p=0.019,). Interestingly, sCD14 was also associated with NO2^-/NO3^- in this group (r=0.62, p=0.001, n=22). EDVD also correlated with cyclic GMP (r=0.47, p=0.03, n=22). In summary, circulating sCD14 is associated with endothelial function. While in non-diabetic subjects sCD14 behaves as an acute phase reactant, its role in type 2 diabetic patients should be further clarified. These findings need to be confirmed in further studies with larger number of patients.

Keywords

Cytokines - atherosclerosis - diabetes / metabolic disorders - inflammatory mediators - ultrasound / diagnosis

• References

• 1 Epstein SE. The multiple mechanisms by which infection may contribute to atherosclerosis development and course.. Circ Res 2002; 90: 2-4.
• 2 Zhu J, Nieto FJ, Horne BD. et al. Prospective study of pathogen burden and risk of myocardial infarction or death.. Circulation 2001; 103: 45-51.
• 3 Prasad A, Zhu J, Halcox JPJ. et al. Predisposition to atherosclerosis by infections. Role of endothelial dysfunction.. Circulation 2002; 106: 184-90.
• 4 Visser MR, Tracy PB, Vercellotti GM. et al. Enhanced thrombin generation and platelet binding on herpes simplex virus-infected endothelium.. Proc Natl Acad Sci USA 1988; 85: 8227-30.
• 5 Key NS, Vercellotti GM, Winkelmann JC. et al. Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression.. Proc Natl Acad Sci USA 1990; 87: 7095-9.
• 6 Kol A, Sukhova GK, Lichtman AH. et al. Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor- and matrix metalloproteinase expression.. Circulation 1998; 98: 300-7.
• 7 Dechend R, Maass M, Gieffers J. et al. Chlamydia pneumoniae infection of vascular smooth muscle and endothelial cells activates NF-B and induces tissue factor and PAI-1 expression: a potential link to accelerated arteriosclerosis.. Circulation 1999; 100: 1369-73.
• 8 Liao W. Endotoxin: possible roles in initiation and development of atherosclerosis.. J Lab Clin Med 1996; 128: 452-60.
• 9 Goyert SM, Ferrero E, Rettig WJ. et al. The CD14 monocyte differentiation antigen maps to a region encoding growth factors and receptors.. Science 1988; 239: 497-500
• 10 Wright SD, Ramos RA, Tobias PS. et al. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein.. Science 1990; 249: 1431-3.
• 11 Sweet JM, Hume DA. Endotoxin signal transduction in macrophages.. J Leukoc Biol 1996; 60: 8-26.
• 12 Harris HW, Grunfeld C, Feingold KR. et al. Human very low density lipoproteins and chylomicrons can protect against endotoxin-induced death in mice.. J Clin Invest 1990; 86: 696-702 Tobias PS, Ulevitch RJ. CD14 is a pattern recognition receptor. Immunity 1994; 1: 509–6.
• 13 Ulevitch RJ, Tobias PS. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin.. Annu Rev Immunol 1995; 13: 437-57.
• 14 Wurfel MM, Hailman E, Wright SD. Soluble CD14 acts as a shuttle in the neutralization of lipopolysaccharide (LPS) by LPS-binding protein and reconstituted high density lipoprotein.. J Exp Med 1995; 181: 1743-54.
• 15 Kitchens RL, Wolfbauer G, Albers JJ. et al. Plasma lipoproteins promote the release of bacterial lipopolysaccharide from the monocyte cell surface.. J Biol Chem 1999; 274: 34116-22.
• 16 Fernández-Real JM, Broch M, Richart C. et al. Circulating soluble CD14 concentration and insulin sensitivity.. J Clin Endocrinol Metab 2003; 88: 1780-4.
• 17 Fernandez-Real JM, Penarroja G, Castro A. et al. Blood Letting in High-Ferritin Type 2 Diabetes: Effects on vascular reactivity.. Diabetes Care 2002; 25: 2249-55
• 18 Celermajer DS, Sorensen KE, Gooch VM. et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.. Lancet 1992; 340: 1111-5.
• 19 Piatti PM, Monti LD, Zavaroni I. et al. Alterations in nitric oxide/cyclic-GMP pathway in nondiabetic siblings of patients with type 2 diabetes.. J Clin Endocrinol Metab 2000; 85: 2416-20.
• 20 Fichtlscherer S, Rosenberger G, Walter DH. et al. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease.. Circulation 2000; 102: 1000-6.
• 21 Greenberg S, Xie J, Wang Y. et al. Tumor necrosis factor-alpha inhibits endothelium-dependent relaxation.. J Appl Physiol 1993; 174: 2394-403.
• 22 Aderka D, Sorkine P, Abu-Abid S. et al. Shedding kinetics of soluble Tumor necrosis factor (TNF) receptors after systemic TNF leaking during isolated limb perfusion. Relevance to the pathophysiology of septic shock.. J Clin Invest 1998; 101: 650-9.
• 23 Fernández-Real JM, Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome.. Endocr Rev 2003; 24: 278-301
• 24 Pieper GM. Enhanced, unaltered and impaired nitric oxide-mediated endothelium-dependent relaxation in experimental diabetes mellitus: importance of disease duration.. Diabetologia 1999; 42: 204-13.
• 25 Albillos A, Rossi I, Cacho G. et al. Enhanced endothelium- dependent vasodilation in patients with cirrhosis.. Am J Physiol 1995; 28: G459-G464.
• 26 Albillos A, de la Hera A, González M. et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.. Hepatology 2003; 37: 208-17.
• 27 Wigg AJ, Roberts-Thomson IC, Dymock RB. et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis.. Gut 2001; 48: 206-11.
• 28 Amar J, Ruidavets JB, Bal Dit Sollier C. et al. Soluble CD14 and aortic stiffness in a population-based study.. J Hypertens 2003; 21: 1869-77.