L.J.H. van Tits

Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2 macrophages: A crucial role for Krüppel-like factor 2

OBJECTIVE Macrophages are key players in atherogenesis because of their properties to form foam cells that produce a large variety of pro-inflammatory mediators. We addressed the potency of phenotypic different macrophages to accumulate oxidized LDL. METHODS AND RESULTS Surprisingly, anti-inflammatory M2 macrophages but not pro-inflammatory M1 macrophages rapidly accumulated oxidized LDL. Simultaneously, expression of Krüppel-like factor 2, a nuclear transcription factor known to suppress inflammation in endothelial cells and monocytes, decreased and the functional phenotype of M2 macrophages shifted towards a pro-inflammatory profile, characterized by higher production of IL-6, IL-8 and MCP-1 and lower expression of IL-10 upon stimulation with LPS. In contrast, Krüppel-like factor 2 expression and the phenotype of M1 macrophages remained largely unchanged upon oxidized LDL exposure. Downregulation of Krüppel-like factor 2 expression of M2 macrophages using siRNA technology led to a significant increase of LPS-induced MCP-1 secretion. CONCLUSIONS We show that (1) anti-inflammatory M2 macrophages are more susceptible to foam cell formation than pro-inflammatory M1 macrophages, (2) exposure to oxidized LDL renders M2 macrophages pro-inflammatory, and (3) Krüppel-like factor 2 is involved in the enhanced secretion of MCP-1 by M2 macrophages loaded with oxidized LDL. The phenotype switch of M2 macrophages from an anti- to a pro-inflammatory profile may play an important role in pathogenesis of atherosclerosis, and could represent a novel therapeutic target.

Plasma annexin A5 and microparticle phosphatidylserine levels are elevated in sickle cell disease and increase further during painful crisis.

Expression of phosphatidylserine (PS) on the membrane surface of red blood cells and circulating microparticles (MP) plays an important role in etiology of the hypercoagulable state of sickle cell disease (SCD), as well as in the reduced red cell life span and adhesive interactions between red cells and endothelium. Annexin A5, an intracellular protein abundantly present in endothelial cells and platelets, exhibits high affinity for PS and has been shown to inhibit several of these PS-mediated pathophysiological processes. We determined plasma annexin A5 levels and MP-associated procoagulant activity, a measure of MP-PS exposure, in 17 sickle cell patients (12 HbSS and 5 HbSC) in steady state and at presentation with a painful crisis. Twenty-five HbAA blood donors served as controls. Both annexin A5 and MP-PS were highest in HbSS patients (5.7 ng/mL, IQR 3.7-7.6 and 37.9 nM, IQR 31.9-69.8) as compared to HbSC patients (1.8 ng/mL, IQR 1.7-7.6 and 20.9 nM, IQR 10.9-29.6) and healthy controls (2.5 ng/mL, IQR 1.4-4.4 and 13.1 nM, IQR 9.5-18.5) (p=0.01 and p<0.001, respectively). At presentation with a painful crisis, annexin A5 and MP-PS had increased in 16 of 17 patients (p=0.001 and p<0.001, respectively). Most interestingly, in 7 HbSS patients the proportional increase in MP-PS exposure was higher than the proportional increase in plasma annexin A5 concentration, leading to lower annexin A5/MP-PS ratio of HbSS patients during crisis than HbAA controls (0.0027 (0.0017-0.0049) vs 0.0048 (0.0027-0.0085), p=0.05). In conclusion, patients with SCD have elevated plasma levels of annexin A5- and PS-exposing MP. During crisis both levels increase, but in most HbSS patients MP-PS exposure increases more than annexin A5. Future studies must address a potential role of annexin A5 in modulating PS-related pathophysiological processes in SCD.

Impact of waist circumference versus adiponectin level on subclinical atherosclerosis

Abstract.  Holewijn S, den Heijer M, van Tits LJ, Swinkels DW, Stalenhoef AFH, de Graaf J (Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands). Impact of waist circumference versus adiponectin level on subclinical atherosclerosis. A cross‐sectional analysis in a sample from the general population. J Intern Med 2010; 267:588–598.

Endothelial function in familial combined hyperlipidaemia

Background  Familial combined hyperlipidaemia (FCH) is characterized by dyslipidaemia, visceral obesity and insulin resistance, and is associated with an increased intima‐media thickness (IMT) and an increased risk for cardiovascular disease. In the present study, we investigated whether FCH is associated with early functional vascular wall changes, as represented by endothelial dysfunction, and we determined whether endothelial function in FCH is related to any of the cardiovascular risk factors associated with the FCH phenotype, or to the (increased) IMT.

The effect of statin therapy on plasma high‐density lipoprotein cholesterol levels is modified by paraoxonase‐1 in patients with familial hypercholesterolaemia

Objectives.  Statins reduce low‐density lipoprotein cholesterol (LDL‐C) and can raise high‐density lipoprotein cholesterol (HDL‐C). HDL‐bound paraoxonase‐1 (PON1) is associated with variations in plasma HDL‐C, and may, therefore, contribute to changes of HDL‐C during statin therapy.

Impact of waist circumference versus adiponectin level on subclinical atherosclerosis: A cross-sectional analysis in a sample from the general population

Abstract.  Holewijn S, den Heijer M, van Tits LJ, Swinkels DW, Stalenhoef AFH, de Graaf J (Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands). Impact of waist circumference versus adiponectin level on subclinical atherosclerosis. A cross‐sectional analysis in a sample from the general population. J Intern Med 2010; 267:588–598.

Original Article: Impact of waist circumference versus adiponectin level on subclinical atherosclerosis: A cross-sectional analysis in a sample from the general population

Abstract.  Holewijn S, den Heijer M, van Tits LJ, Swinkels DW, Stalenhoef AFH, de Graaf J (Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands). Impact of waist circumference versus adiponectin level on subclinical atherosclerosis. A cross‐sectional analysis in a sample from the general population. J Intern Med 2010; 267:588–598.