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European Heart Journal Advance Access originally published online on June 8, 2006
European Heart Journal 2006 27(13):1605-1609; doi:10.1093/eurheartj/ehl079
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

TNF-{alpha} induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-{gamma} agonist pioglitazone

Fabrice M.A.C. Martens1, Ton J. Rabelink2, Jos op 't Roodt2, Eelco J.P. de Koning2 and Frank L.J. Visseren1,*

1 Department of Internal Medicine, Section of Vascular Medicine, University Medical Center Utrecht, F02.126, Heidelberglaan 100, PO Box 85500, 3508 GA Utrecht, The Netherlands
2 Department of Nephrology, Leiden University Medical Center, The Netherlands

Received 10 October 2005; revised 24 April 2006; accepted 19 May 2006; online publish-ahead-of-print 8 June 2006.

* Corresponding author. Tel: +31 30 2509111; fax: +31 30 2518328. E-mail address: F.L.J.Visseren{at}umcutrecht.nl


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims Inflammation contributes to the pathogenesis of cardiovascular disease. Tumour necrosis factor (TNF)-{alpha}, in particular, is a key mediator of inflammation and vascular dysfunction and progression of atherosclerotic disease. Pioglitazone, a peroxisome proliferator-activated receptor-{gamma} agonist, not only improves insulin sensitivity, but may also have anti-inflammatory effects. The aims of this study were to investigate the acute effects of local intra-arterial infusion with low-dose TNF-{alpha} on resistance vessel endothelial function in type 2 diabetes and to determine whether short-term pioglitazone treatment protects against vascular dysfunction induced by this inflammatory stimulus.

Methods and results A randomized, parallel, placebo-controlled, double blind trial with 30 mg pioglitazone once daily for 4 weeks was performed in 16 male patients with recently diagnosed type 2 diabetes. Forearm plethysmography (FBF) was used to evaluate the effect on resistance vessel responses of intra-arterial administration of serotonin (NO-dependent vasodilation) and nitroprusside (endothelium-independent vasodilation) followed by another FBF-measurement during the second hour of intra-arterial infusion with TNF-{alpha} (10 ng/100 mL forearm volume/min for 2 h). Endothelial-dependent FBF of type 2 diabetic patients was significantly impaired (25.4%) by intra-arterial TNF-{alpha} infusion (P=0.01), whereas nitroprusside-induced vasodilation did not change. Treatment with pioglitazone for 4 weeks completely blocked TNF-{alpha}-induced impairment of endothelial-dependent FBF compared with placebo. No significant changes in plasma concentrations of TNF-{alpha}, interleukin-6, soluble TNF-{alpha}-receptors, or CD40L were observed.

Conclusion Pioglitazone treatment can convey direct protection against cytokine (TNF-{alpha})-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes.

Key Words: Diabetes mellitus • Endothelial function • Inflammation • Pioglitazone • Tumour necrosis factor-{alpha}


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
The metabolic syndrome, which involves a cluster of cardiovascular risk factors including hypertension, obesity, glucose intolerance, endothelial dysfunction, dyslipidaemia, and a pro-inflammatory state, is generally considered to be of major importance in the pathophysiology of type 2 diabetes and cardiovascular complications.1 Endothelial activation is considered the transducer by which risk factors lead to progression of atherosclerosis. It is present in patients with increased cardiovascular risk including the metabolic syndrome2 and is a predictor for development of cardiovascular events.3 Endothelial activation is characterized by decreased availability of endothelium-derived nitric oxide (NO) and can be assessed clinically by impaired forearm blood flow (FBF) to NO-agonists.

Low-grade chronic vascular inflammation contributes to the pathogenesis of cardiovascular disease. Elevated levels of pro-inflammatory proteins are predictive for both cardiovascular disease and type 2 diabetes.4 The pro-inflammatory cytokines, tumour necrosis factor-{alpha} (TNF-{alpha}), and interleukin-6 (IL-6), in particular, are elevated in patients with endothelial dysfunction and ischaemic heart disease.5,6 TNF-{alpha} downregulates mRNA for endothelial nitric oxide synthase by shortening its half-life in endothelial cells.7 In addition, in vivo intra-arterial TNF-{alpha} causes an acute local vascular inflammation that is associated with impaired endothelium-dependent vasomotion in young healthy non-smoking men because of an acute local vascular-wall inflammation confirmed by the local rise of IL-6.8 Another recent study in healthy lean male volunteers showed impairment of endothelium-dependent vasodilation upon intra-arterial TNF-{alpha} infusion.9

Thiazolidinediones (TZDs), such as pioglitazone and troglitazone, are a class of oral anti-hyperglycaemic agents and ligands for peroxisome proliferator-activated receptors (PPARs), in particular, PPAR-{gamma}. These nuclear transcription factors are involved in glucose homeostasis, lipid and lipoprotein metabolism, and adipogenesis. TZDs improve glycaemic control by increasing insulin sensitivity, but may also have potential anti-inflammatory effects.10

Therefore, in the present study, we first investigated the effect of TNF-{alpha} on endothelium-dependent vasodilation, and secondly the effects of short-term pioglitazone treatment on TNF-{alpha}-induced endothelial dysfunction in patients with type 2 diabetes mellitus.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Subjects
16 male, non-smoking patients with recently diagnosed type 2 diabetes were recruited. All patients were treated with oral anti-hyperglycaemic agents (seven patients with sulphonylurea derivates, three patients with metformin only, and seven patients with a combination of metformin and sulphonylurea derivates) which was continued during the study. Subjects with very poor glycaemic control (HbA1c>9%) were excluded. Other exclusion criteria were the presence of macro- or microvascular disease and the use of vasoactive medication (e.g. beta-blockers, calcium entry blockers, ACE-inhibitors, angiotensin type 1 receptor blockers, statins, aspirin, non-steroidal inflammatory drugs). None of the patients had a history of cardiovascular diseases. The patients were also participants in one of our previous studies.11 The protocol was approved by the Ethical Review Board of the University Medical Center Utrecht (UMCU). All subjects gave written informed consent. Measurements were carried out in accordance with the local institutional guidelines in a Good Clinical Practice-certified unit.

Study design
The study was a prospective, randomized, parallel, placebo-controlled, double blind trial. Patients eligible to take part in the study were randomized in two patient groups: eight patients received placebo in addition to their current oral anti-hyperglycaemic agents for 4 weeks first followed by measurement of forearm vascular function without intra-arterial TNF-{alpha} infusion and secondly directly followed by measurement of forearm vascular function during the second hour of intra-arterial TNF-{alpha} infusion [10 ng/100 mL forearm volume (FAV)/min for 2 h]; eight patients received pioglitazone 30 mg once daily (Eli Lilly, Indianapolis, IN, USA) in addition to their current oral anti-hyperglycaemic agents for 4 weeks first followed by measurement of forearm vascular function without intra-arterial TNF-{alpha} infusion and secondly directly followed by measurement of forearm vascular function during the second hour of intra-arterial TNF-{alpha} infusion (10 ng/100 mL FAV/min for 2 h). At the end of each 4-week treatment period, laboratory parameters were determined. Patients were instructed to fast for at least 10 h prior to the tests. No study medication or other medication was used on the morning of the study day.

Assessment of vascular function
Patients and study staff were blinded for the treatment patients received. Experiments were performed in a temperature-controlled room (22–24°C) in the morning. All vascular function tests after pioglitazone and placebo treatment were performed at the same time for each individual in order to exclude daytime variability. Upon arrival, patients were asked to rest in a supine position for 20 min before insertion of intra-arterial and intravenous cannula, blood withdrawal for laboratory measurements, and determination of FBF using venous occlusion plethysmography.

For assessment of FBF by venous occlusion plethymography (Hokanson EC-4, Bellevue, WA, USA), both forearms were supported above heart level. The brachial artery of the non-dominant arm was cannulated with a 20-gauge catheter (Arrow International, USA) after local anaesthesia. Bilateral FBF was determined using mercury-in-silastic strain gauges and a microcomputer-based, R-wave-triggered system for online monitoring according to established methods.12 Intra-arterial blood pressure was continuously monitored. Baseline measurements were performed at least 45 min after cannulation of the brachial artery in order to allow stabilization of baseline blood flow. Vasoactive agents were dissolved in NaCl 0.9% and infused at a constant rate of 90 mL/h. All infusates were prepared in our hospitals's pharmacy department in accordance to GMP guidelines.

Sequential infusions of vasoactive agents were performed. Serotonin (5-HT, Sigma Chemicals, St Louis, MO, USA) was infused into the brachial artery at increasing doses of 0.6, 1.8, and 6.0 ng/100 mL FAV/min. This protocol has previously been shown to cause a dose-dependent increase in endothelium-dependent, NO-mediated vasodilation.13 Sodium nitroprusside (SNP) (Merck, Germany) was infused at increasing doses of 20, 60, 180, and 600 ng/100 mL FAV/min to assess endothelium-independent vasodilation. Serotonin and SNP infusions were performed in random order to avoid any bias related to the order of drug infusion. Each dose was infused for 5–7 min and only during the last 2–3 min FBF was recorded. Five-minute intervals were applied between each dose. In order to allow recovery of FBF after administration of a vasoactive agent, a 20 min rest between infusions of different vasoactive agents was given. Average values of FBF of the cannulated and control arm were obtained from the last four to six consecutive recordings of each infusion period. The ratio of flow in the cannulated measurement (M) and non-cannulated control (C) arm was calculated for each recording (M:C ratio). The FBF for each dose is expressed as the percentage change of M:C ratio from baseline M:C ratio (M:C%). The FBF analyses (post-measurement) were performed by a lab technician blinded for the treatment.

TNF-{alpha} infusion
Human recombinant TNF-{alpha} (10 ng/100 mL FAV/min Tasonermin, Boehringer-Ingelheim, Germany; 1/8 of dose is used in healthy young volunteers8) was infused in the cannulated brachial artery for 2 h. During the second hour of TNF-{alpha} infusion, serotonin and SNP infusions were performed as well as FBF measurements. Blood was drawn from the infused arm, 60 and 120 min after the start of intra-arterial TNF-{alpha} infusion, for measurements of TNF-{alpha} and IL-6 concentrations. Blinded sham control with an intra-arterial salt infusion was not performed due to the invasive nature of the procedure.

Laboratory assessment
At the end of each 4-week treatment period, fasting blood was drawn before the start of FBF measurements and plasma was frozen at –20°C until further analysis. Glucose, creatinine, serum alanine transferase, serum aspartate transferase, total cholesterol, triglycerides, and high density lipoprotein (HDL) cholesterol (HDL-C) were measured by standard enzymatical laboratory methods (Vitros 250, Johnson/Johnson). Low density lipoprotein (LDL) cholesterol (LDL-C) was calculated with the Friedewald formula. HbA1c and free fatty acids (FFA) were photometrically performed (Hitachi 911, Roche). Insulin levels were determined with an immunological method (Immulite 2000; Diagnostic Prod Corp.). HOMA-R was calculated [fasting glucose (mmol/L)xfasting insulin (mU/mL)/22.5]. Measurements of plasma TNF-{alpha}, soluble TNF-{alpha} receptors 60 and 80 kDa and IL-6 were performed with a commercially available high-sensitive kits (ELISA, R&D Systems Inc./minimum detectable doses resp.: 0.06, 0.2, 0.43, and 0.016 pg/mL). Measurement of circulating sCD40L was also performed with a commercially available high-sensitive kit (ELISA, BenderMed Systems/minimum detectable dose: 0.005 ng/mL).

Statistical analysis
Results from vascular function tests and laboratory analysis are expressed as mean±standard error. Differences in metabolic parameters between both treatments were analysed with (un-)paired two-sided t-tests. In the case of non-normal distribution, the Wilcoxon-signed rank test was used. FBF analyses were done by repeated measures analysis, using general linear model. Statistical significance was taken at the 5% level.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Anthropometric, haemodynamic, and metabolic baseline parameters
Table 1 shows the anthropometric, haemodynamic, inflammatory, and metabolic baseline parameters of both groups.


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  		Table 1 Baseline characteristics

 
During TNF-{alpha}-infusion, the intra-arterial TNF-{alpha} concentration increased. No significant changes were observed in anthropometric, haemodynamic, metabolic, and inflammatory parameters after 4 weeks of pioglitazone or placebo treatment (Table 2). Oedema did not occur in any patient on pioglitazone treatment. Pioglitazone treatment was not associated with liver enzyme abnormalities.


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  		Table 2 Clinical characteristics after treatment

 
Effects of pioglitazone and intra-arterial TNF-{alpha} infusion on FBF
Intra-arterial TNF-{alpha} infusion had no effects on heart rate or blood pressure. Basal FBF was similar in all groups.

The serotonin-induced endothelial-dependent FBF of patients treated with placebo for 4 weeks was impaired by intra-arterial TNF-{alpha} infusion (P=0.01) (Figure 1A).


Figure 0791
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  		Figure 1 (A) Endothelial-dependent serotonin-induced vasodilation of the forearm. Values are mean±SEM. Filled diamond indicates placebo (n=8). Filled square indicates pioglitazone (n=8). Cross indicates placebo+TNF-{alpha} infusion (10 ng/min for 2 h) (n=8). Filled triangle indicates pioglitazone+ TNF-{alpha} infusion (10 ng/min for 2 h) (n=8). *P-value of 0.01 is reported for the comparison between placebo with and without TNF-{alpha} infusion; P-value of 0.012 is reported for the comparison between the two randomized groups (placebo vs. pioglitazone) of the differences between with and without TNF-{alpha} infusion. Analyses were done by repeated measures analysis, using general linear model. (B) Endothelial-independent nitroprusside-induced vasodilation of the forearm. Values are mean±SEM. Filled diamond indicates placebo (n=8). Filled square indicates pioglitazone (n=8). Cross indicates placebo+TNF-{alpha} infusion (10 ng/min for 2 h) (n=8). Filled triangle indicates pioglitazone+TNF-{alpha} infusion (10 ng/min for 2 h) (n=8). NS, no comparisons are significant. Analyses were done by repeated measures analysis, using general linear model.

 
After treatment with pioglitazone for 4 weeks followed by an intra-arterial TNF-{alpha} infusion, the serotonin-induced endothelium-dependent vasodilation in the forearm vascular bed stayed at the level of the serotonin-induced endothelium-dependent vasodilation of the placebo group or the pioglitazone group without intra-arterial TNF-{alpha} infusion. In comparison between the two randomized groups (placebo vs. pioglitazone) of the differences between with and without TNF-{alpha} infusion, the delta of the serotonin-induced endothelium-dependent vasodilation in the forearm vascular bed of the placebo-treated patients was significantly more than the serotonin-induced endothelium-dependent vasodilation in the forearm vascular bed of the pioglitazone-treated patients (P=0.012) (Figure 1A).

Administration of the endothelium-independent vasodilator nitroprusside caused an increase in FBF that was at the same level in the pioglitazone group as it was in the placebo group, indicating that there was no alteration in large vessel vascular smooth muscle cell (VSMC) responsiveness to NO (Figure 1B). Furthermore the endothelial-independent nitroprusside-induced vasodilation did not change indicating that there was no alteration of large vessel VSMC responsiveness to NO (Figure 1B).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
Inflammation contributes to the pathogenesis of cardiovascular disease and elevated levels of pro-inflammatory proteins are predictive of both cardiovascular disease and type 2 diabetes.4 Especially in obese individuals, TNF-{alpha} is elevated and is associated with ischaemic heart disease and endothelial dysfunction.5,6 The main outcome of the present study is that low-dose intra-arterial TNF-{alpha} infusion induces an acute impairment of endothelial function in type 2 diabetes and that (short-term) pioglitazone treatment blocks this impairment completely independent of metabolic changes.

In vitro TNF-{alpha} plays a role in acute coronary syndromes by increasing the expression of adhesion molecules on the endothelial cell surface and ensuing the recruitment of inflammatory cells and by decreasing the viability of VSMCs. In agreement with such mechanisms, TNF-{alpha} levels have been associated with plaque instability by decreasing VSMC viability.14 In vivo previous studies showed impairment of endothelium-dependent vasodilation in healthy subjects by low-dose intra-arterial TNF-{alpha} infusion.8 Recently, it is shown that physiological concentrations of insulin together with TNF-{alpha} gives endothelin-1-dependent vasoconstriction via c-Jun N-terminal kinase.15 Type 2 diabetic patients already have endothelial dysfunction and it could therefore be hypothesized that inflammatory stimuli such as TNF-{alpha} do not further affect endothelial function. However, in our study, we now show that raising the intra-arterial TNF-{alpha} concentration in type 2 diabetes locally, to levels that are towards the range of the levels found in conditions such as congestive heart failure16 and acute coronary syndromes,17 further impairs endothelium-dependent vasodilation. This effect appeared to be endothelium-specific, as vasodilation to nitroprusside was unaltered. Treatment with pioglitazone for 4 weeks completely protected against TNF-{alpha}-induced depression of endothelium-dependent vasodilation. It should be noticed that baseline levels of cytokines and TNF-{alpha} were not affected by pioglitazone treatment nor was there any change in metabolic indices in this short-term study. This is not unexpected, as usually the metabolic effects of TZD treatment only become apparent after 8 weeks of treatment.18,19 Nevertheless, basal endothelial function was also restored to normal values (Figure 1A).

These data indicate that pioglitazone specifically and directly changed endothelial function, particularly the endothelial responsiveness to TNF-{alpha}. Indeed, the PPAR-{gamma} isoform is expressed in endothelial cells and its activation has been associated with an enhanced NO availability20–22 and a reduced potential of endothelial cells to switch to an inflammatory phenotype.23–25 There appears to be a generalized repression of NF-{kappa}B, CCAAT/enhancer-binding protein, and activator protein-1-mediated transcription of inflammatory genes.26,27 The exact mechanism is still unknown, but probably involves increased levels of co-repressor molecules or transcriptional superregulation, for example, by chromatin remodelling, as has been described for activation of other nuclear hormone receptors.28,29 In addition, endothelial release of the vasoconstrictor peptide endothelin-1 is suppressed by TZDs.30

The direct vascular anti-inflammatory properties of TZDs have previously been demonstrated in animal models. For example, angiotensin-II infusion in rats resulted in endothelial dysfunction, increased media/lumen ratio, and vascular inflammation. All these changes were abrogated by TZD treatment independently of metabolic effects, suggesting direct interference of TZDs with signalling cascades that lead to these events.31 Our current study extends these properties of TZDs to humans with increased cardiovascular risk. These observations may provide an explanation for some of the recent findings where TZD treatment could reduce the progression of intima-media thickness,32 a proxy for atherosclerotic burden and cardiovascular risk,33 in patients with coronary artery disease (CAD) but without diabetes. In these studies, only minimal changes in metabolic parameters were observed.

We only included subjects using oral anti-hyperglycaemic agents. Because insulin has profound effects on the vasculature, caution should be taken to extrapolate our results to patients with type 2 diabetes using pioglitazone in combination with insulin. In addition, patients using vasoactive medication were excluded from our study, although it would also be interesting to study the additional benefits of pioglitazone in these patients.

In conclusion, pioglitazone treatment can convey direct protection against cytokine (TNF-{alpha})-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
We gratefully acknowledge Laura Splint for her laboratory analyses under the supervision of G. Dallinga-Thie. The Dutch affiliate of Eli Lilly and Company financially supported this study by an unrestricted grant and provided the study medication.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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