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Pål Aukrust

Publications and source records attributed to Pål Aukrust.

At least 19 recordsLinked to original sources
PubMed2005

Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, is elevated in coronary artery disease and is reduced during statin therapy.

OBJECTIVE: Recent data derived primarily from studies in animal models suggest that fractalkine (CX3CL1) and its cognate receptor, CX3CR1, play a role in atherogenesis. We, therefore, hypothesized that enhanced CX3CL1/CX3CR1 expression may promote atherogenesis in patients with coronary artery disease (CAD). METHODS AND RESULTS: We examined the plasma levels of CX3CL1 and CX3CR1 expression in peripheral blood mononuclear cells (PBMC) in various CAD populations (30 patients with previous myocardial infarction, 40 patients with stable angina, 40 patients with unstable angina, and a total of 35 controls) and used various experimental approaches to characterize CX3CL1-mediated leukocyte responses. We found that the plasma levels of CX3CL1 are greatly increased in CAD, particularly in unstable disease. The parallel increase of CX3CR1 expression in PBMC was predominantly attributable to an expansion of the (CX3CR1+)(CD3+)(CD8+) T cell subset and was associated with enhanced chemotactic, adhesive, and inflammatory responses to CX3CL1. Statin therapy for 6 months reduced the expression of CX3CL1 and CX3CR1, reaching statistical significance for both parameters only during aggressive (atorvastatin, 80 mg qd) but not conventional (simvastatin, 20 mg qd) therapy. Consequently, the functional responses of the PBMC to CX3CL1 including migration, adhesion, and secretion of interleukin-8 were attenuated by the treatments. CONCLUSIONS: Our results suggest that the CX3CL1/CX3CR1 dyad may contribute to atherogenesis and plaque destabilization in human CAD.

Angina, Unstable↗
PubMed2005

Enhanced plasma levels of LIGHT in unstable angina: possible pathogenic role in foam cell formation and thrombosis.

BACKGROUND: Numerous studies have demonstrated the ability of oxidized LDL [(ox)LDL] to promote an inflammatory response in macrophages. Several inflammatory mediators have been reported to increase after oxLDL stimulation of such cells, but their relative importance is still unknown. In the present study, we used microarrays to identify genes in THP-1 macrophages that were upregulated by oxLDL. METHODS AND RESULTS: Our main findings were as follows. In a microarray screening experiment, we identified LIGHT, a ligand in the tumor necrosis factor superfamily, as one of the genes that were markedly upregulated in oxLDL-stimulated THP-1 macrophages. We showed significantly raised plasma levels of LIGHT in patients with stable angina (n=40) and particularly in those with unstable angina (n=40) compared with healthy controls (n=20), which underscores the clinical relevance of the in vitro finding. We also showed that LIGHT enhanced lipid accumulation in oxLDL-stimulated THP-1 macrophages, possibly through upregulation of class A scavenger receptor (SR-A). This increased lipid accumulation was accompanied by enhanced expression of tissue factor and plasminogen activator inhibitor-1, as well as enhanced thrombin formation, transforming macrophages into a prothrombotic phenotype. The LIGHT-mediated increase in SR-A, tissue factor, and plasminogen activator inhibitor-1 was also seen in human monocyte-derived macrophages. Finally, the LIGHT-mediated enhancement of SR-A and TF expression appears to involve nuclear factor-kappaB activation. CONCLUSIONS: These findings suggest that LIGHT could serve as a molecular link between lipid metabolism, inflammation, and thrombus formation, which are all features of atherosclerotic plaques.

Aged↗
PubMed2005

Review of trials in chronic heart failure showing broad-spectrum anti-inflammatory approaches.

Accumulating evidence indicates that inflammatory mediators are important in the pathogenesis of chronic heart failure (CHF), contributing to cardiac remodeling and peripheral vascular disturbances. Several studies have shown increased levels of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 in patients with CHF in both plasma and circulating leukocytes as well as in the failing myocardium itself. Importantly, this increase in inflammatory mediators does not seem to be accompanied by a corresponding increase in anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta, resulting in an inflammatory imbalance in the cytokine network. Traditional cardiovascular drugs seem to have little influence on the cytokine network in patients with CHF, and immunomodulatory therapy in addition to "optimal" cardiovascular treatment regimens has emerged as an option. Thus, several animal studies as well as some clinical pilot trials have suggested that downregulation of inflammatory cytokines may improve cardiac performance. On the other hand, preliminary results from placebo-controlled anti-TNF studies suggest no effect, or even an adverse effect of anti-TNF therapy on mortality and hospitalization. Although somewhat disappointing, these negative results do not necessarily argue against the cytokine hypothesis. These studies only underscore the difficulties and challenges in developing treatment modalities that can modulate the cytokine network in patients with CHF, resulting in anti-inflammatory and beneficial net effects. Further research in this area will have to more precisely identify the most important "actors" in the immunopathogenesis of CHF to improve the immunomodulatory treatment regimens in this disorder.

Animals↗
PubMed2005

Antiinflammatory effects of tetradecylthioacetic acid involve both peroxisome proliferator-activated receptor alpha-dependent and -independent pathways.

OBJECTIVE: Tetradecylthioacetic acid (TTA) is a hypolipidemic antioxidant with immunomodulating properties involving activation of peroxisome proliferator-activated receptors (PPARs). Human endothelial cells express PPARs. We hypothesized that TTA could modulate endothelial cell activation at least partly through PPAR-related mechanisms. METHODS AND RESULTS: We explored this hypothesis by different experimental approaches involving both in vitro studies in human endothelial cells (HUVECs) and in vivo studies in humans and PPAR-alpha-/- mice. Our main findings were as follows: (1) TTA suppressed the tumor necrosis factor alpha-induced expression of vascular cell adhesion molecule 1 (VCAM-1) and interleukin 8 (IL-8) in HUVECs. (2) No TTA-mediated attenuation of VCAM-1 and chemokine expression was seen in the liver of PPAR-alpha-/- mice. (3) Whereas TTA markedly enhanced PPAR-alpha-target genes in the liver of wild-type, but not of PPAR-alpha-/-, mice, no such effect on PPAR-alpha-target genes was seen in HUVECs. (4) The relevance of our findings to human disease was suggested by a TTA-mediated downregulation of serum levels of soluble VCAM-1 and IL-8 in psoriasis patients. CONCLUSIONS: We show that TTA has the ability to attenuate tumor necrosis factor alpha-mediated endothelial cell activation, further supporting antiinflammatory effects of this fatty acid, possibly involving both PPAR-alpha-dependent and -independent pathways.

Adult↗
PubMed2005

Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure.

BACKGROUND: Persistent inflammation appears to play a role in the development of heart failure (HF). Osteoprotegerin (OPG), the receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) are newly discovered members of the tumor necrosis factor superfamily that are critical regulators in bone metabolism but appear also to be involved in immune responses. We hypothesized that the OPG/RANK/RANKL axis could be involved in the pathogenesis of heart failure (HF), and this hypothesis was investigated in both experimental and clinical studies. METHODS AND RESULTS: Our main and novel findings were as follows: (1) In a rat model of postinfarction HF, we found persistently increased gene expression of OPG, RANK, and RANKL in the ischemic part of the left ventricle (LV) and, for OPG, in the nonischemic part that involved both noncardiomyocyte and in particular cardiomyocyte tissue. (2) Enhanced myocardial protein levels of OPG, RANK, and RANKL, in particular, were also seen in human HF, and using immunohistochemistry, we localized these mediators to cardiomyocytes within the LV in both experimental and clinical HF. (3) In human HF, we also found increased systemic expression of RANKL (T cells and serum) and OPG (serum), with increasing levels according to functional, hemodynamic, and neurohormonal disease severity. (4) RANKL increased total matrix metalloproteinase activity in human fibroblasts, which indicates a matrix-degrading net effect and suggests a potential mechanism by which enhanced RANKL expression in HF may contribute to LV dysfunction. CONCLUSIONS: These findings suggest a potential role for known mediators of bone homeostasis in the pathogenesis of HF and possibly represents new targets for therapeutic intervention in this disorder.

Adult↗
PubMed2005

Low mannose-binding lectin and increased complement activation correlate to allograft vasculopathy, ischaemia, and rejection after human heart transplantation.

AIMS: Transplant-associated coronary artery disease (TxCAD) is a major cause of post-transplant graft failure. The aim of this study was to investigate a possible role of mannose-binding lectin (MBL) deficiency and complement activation in TxCAD. METHODS AND RESULTS: In a prospective study of heart transplant recipients (n=38) with a follow-up of 5.3+/-1.3 years (range: 0.9-6.6), angiographically verified TxCAD (n=6) was correlated to plasma MBL, complement activation, and endothelial activation (soluble E-selectin). MBL deficiency (<100 ng/mL) was detected in 3/6 patients with TxCAD and in 3/32 with non-TxCAD (Kaplan-Meier, P=0.020). Furthermore, one or more acute rejection episodes were observed in 6/6 of the MBL-deficient patients and in 15/32 of the MBL-sufficient patients (chi(2); P=0.016). Complement activation (C4bc) correlated with soluble E-selectin (r=0.36; P=0.027), both being significantly higher in patients with ischaemia detected in the first biopsy (C4bc: 13.4+/-6.1 AU/mL; E-selectin: 96+/-13 ng/mL) than in those without ischaemia (C4bc: 6.3+/-0.5; E-selectin: 51+/-6; P=0.037 and 0.002). Finally, terminal complement complex correlated closely with mortality (P=0.002). CONCLUSION: Low MBL was related to the development of TxCAD and acute rejection and increased complement activation correlated to histopathologic ischaemia and mortality after heart transplantation.

Adult↗
PubMed2005

Down-regulated expression of PPARalpha target genes, reduced fatty acid oxidation and altered fatty acid composition in the liver of mice transgenic for hTNFalpha.

The present study investigated the hepatic regulation of fatty acid metabolism in hTNFalpha transgenic mice. Reduced hepatic mRNA levels and activities of carnitine palmitoyltransferase-II (CPT-II) and mitochondrial HMG-CoA synthase were observed, accompanied by decreased fatty acid oxidation, fatty acyl-CoA oxidase and fatty acid synthase (FAS) activities and down-regulated gene expression of mitochondrial acetyl-CoA carboxylase 2 (ACC2). The mRNA levels of peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARdelta were reduced. The hepatic fatty acid composition was altered, with increased amounts of saturated and polyunsaturated fatty acids. The relative amounts of Delta(9) desaturated fatty acids were decreased, as was Delta(9)desaturase mRNA. The CPT-I mRNA level remained unchanged. The PPARalpha targeted genes CPT-II and HMG-CoA synthase are potential regulators of mitochondrial fatty acid oxidation and ketogenesis in hTNFalpha transgenic mice, and the increased propionyl-CoA level found is a possible inhibitor of these processes. Reduced mitochondrial and peroxisomal fatty acid oxidation may explain the increased hepatic triglyceride level induced by TNFalpha. This is not due to de novo fatty acid synthesis as both FAS activity and gene expression of ACC2 were reduced.

Animals↗
PubMed2005

Etanercept or intravenous immunoglobulin attenuates expression of genes involved in post-myocardial infarction remodeling.

OBJECTIVE: Persistently elevated levels of inflammatory cytokines such as tumor necrosis factor (TNF)alpha after acute myocardial infarction (MI) may contribute to maladaptive ventricular remodeling. The aim of the present study was to examine the effects of immunomodulatory therapy with recombinant soluble TNF receptor (TNFR:Fc) or intravenous immunoglobulin (IVIg) on left and right ventricular post-MI remodeling in rats. METHODS AND RESULTS: Adult male Sprague-Dawley rats were subjected to MI by left coronary artery ligation and randomized to treatment with vehicle, TNFR:Fc, or IVIg and sacrificed after 7 days. The main findings were that: (i) TNFR:Fc- and IVIg-treated rats developed less right ventricular (RV) hypertrophy compared to vehicle-treated controls. (ii) LV and arterial pressures in post-MI rats were not affected by the TNFR:Fc or IVIg treatment. (iii) As determined by real-time RT-PCR, both treatments reduced the expression of the hypertrophy-related genes, atrial natriuretic peptide and the ratio of beta/alpha-myosin heavy chains, and genes related to extracellular matrix remodeling (i.e., collagens I and III, matrix metalloproteinase [MMP]-2 and its tissue inhibitor TIMP-1) in the non-ischemic segment of LV and, in particular, in the RV. (iv) Treatment with IVIg, but not TNFR:Fc, reduced MMP-2 zymographic activity in the RV and the expression of genes for TNFalpha and monocyte chemoattractant protein-1. CONCLUSION: Therapy targeted directly against TNFalpha (i.e., TNFR:Fc) and a more general immunomodulatory approach (i.e., IVIg) in the acute phase of MI attenuates the cardiac remodeling process and expression of genes that are involved. These findings raise the possibility that initiation of immunomodulatory therapy post-MI could be beneficial in preventing the later development of heart failure.

Animals↗
PubMed2005

Soluble CD40 ligand in acute and chronic heart failure.

AIMS: Inflammatory cytokines may play a pathogenic role in heart failure (HF). CD40-CD40 ligand (CD40L) interactions are important in atherogenesis and based on its role in inflammation we sought to evaluate the role of CD40L in human HF. METHODS AND RESULTS: Serum levels of soluble (s) CD40L were measured in 236 patients with acute HF following myocardial infarction, treated with either angiotensin-converting enzyme (ACE)-inhibition or angiotensin II blockade and followed for 2 years, and in 116 patients with chronic HF. Our main findings were: (i) patients with acute HF had increased sCD40L levels, particularly those with severe HF, diabetes, or hypertension; (ii) when these patients were followed longitudinally, persistently raised sCD40L levels were found throughout the observation period with no effect of captopril or losartan; (iii) the increase in sCD40L during follow-up was not seen in patients receiving warfarin therapy; (iv) patients with chronic HF also had raised sCD40L, significantly correlated with clinical severity, neurohormonal dysregulation, and left ventricular dysfunction; (v) studies from different blood compartments suggest that the vasculature of lower extremities and the failing myocardium itself may produce and secrete sCD40L in chronic HF. CONCLUSION: Our findings may suggest a pathogenic role for enhanced CD40-CD40L interactions in human HF.

Acute Disease↗
PubMed2005

Impaired base excision repair and accumulation of oxidative base lesions in CD4+ T cells of HIV-infected patients.

Several studies have reported enhanced oxidative stress in patients with HIV infection. An important pathophysiologic consequence of increased oxidative stress is endogenous DNA damage, and the base excision repair pathway is the most important mechanism to withstand such deleterious effects. To investigate the role of base excision repair in HIV infection, we examined 7,8-dihydro-8-oxoguanine (8-oxoG) levels as a marker of oxidative DNA damage and DNA glycosylase activities in CD4(+) and CD8(+) T cells of HIV-infected patients and controls. These results showed that the HIV-infected patients, particularly those with advanced disease, had increased levels of 8-oxoG in CD4(+) T cells and marked declines in DNA glycosylase activity for the repair of oxidative base lesions in these cells. In contrast, CD8(+) T cells from HIV-infected patients, with 8-oxoG levels similar to those in healthy controls, showed enhanced capacity to repair oxidative DNA damage. Finally, highly active antiretroviral therapy induced increased glycosylase activity in CD4(+) T cells and normalized 8-oxoG levels. This imbalance between the accumulation of oxidative DNA damage and the capacity to repair such lesions in CD4(+) T cells may represent a previously unrecognized mechanism involved in the numerical and functional impairment of CD4(+) T cells in patients with HIV infection.

Adult↗
PubMed2005

Inflammatory response and re-stenosis after percutaneous coronary intervention in heart transplant recipients and patients with native atherosclerosis.

BACKGROUND: The clinical benefit of percutaneous coronary intervention (PCI) in heart transplant recipients (HTRs) with coronary allograft vasculopathy (CAV) has been questioned. We investigated the degree of inflammatory reaction during PCI in CAV compared to patients with native atherosclerosis, and the possible relationship between PCI-induced inflammation and the degree of re-stenosis in these 2 patient groups. METHODS: In 11 CAV patients and 10 patients with native atherosclerosis, blood samples were drawn before and 24 hours and 6 months after PCI, and analyzed with regard to hsCRP, MCP-1, components of complement activation, von Willebrand factor (vWf), soluble L-selectin and ICAM-1. Quantitative angiography was performed before and after PCI, and at 6-month follow-up. RESULTS: Baseline levels of hsCRP, vWf and MCP-1 were significantly elevated and levels of L-selectin and ICAM-1 and activation products of the alternative pathway of the complement system were decreased in CAV patients compared to those with native atherosclerosis. PCI induced significant increases of hsCRP in both groups as well as an increase in vWf in native atherosclerosis, whereas a decrease in L-selectin was observed in native atherosclerosis. Plasma levels of MCP-1 correlated with percent stenosis at follow-up in both groups, whereas a correlation between hsCRP and percent stenosis was evident only in patients with native atherosclerosis. There were no differences in rates of re-stenosis between the 2 groups. CONCLUSIONS: HTRs with CAV and patients with native atherosclerosis are characterized by different profiles of immune activation and respond differently to PCI. Nevertheless, an inappropriate inflammatory reactivity may predispose to re-stenosis after PCI in both groups of patients, with pre-procedural inflammation being of particular importance in CAV.

Aged↗
PubMed2005

Inflammatory and anti-inflammatory cytokines in chronic heart failure: potential therapeutic implications.

Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic heart failure (HF) by influencing heart contractility, inducing hypertrophy and promoting apoptosis, contributing to myocardial remodeling. While several stimuli may be operating such as heat shock proteins, microbial antigens and oxidative stress, it seems that the inflammatory response to these stimuli may represent a common final pathogenic pathway in HF regardless of the initial event. Traditional cardiovascular drugs appear to have little influence on the cytokine network, and immunomodulatory therapy has emerged as a possible new treatment modality in HF. Several animal studies and also some clinical studies have suggested that downregulation of inflammation may improve cardiac performance. However, the results from the placebo-controlled anti-tumor necrosis factor studies suggest no improvement or even adverse effects of such therapy. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'. These studies just underscore the challenges in developing treatment modalities that can modulate the cytokine network in HF patients resulting in beneficial net effects. Further research will have to identify more precisely the most important actors in the immunopathogenesis of chronic HF in order to develop more specific immunomodulating agents for this disorder.

Animals↗
PubMed2005

Agents targeting inflammation in heart failure.

Evidence from both experimental and clinical trials indicates that inflammatory mediators are important in the pathogenesis of chronic heart failure (HF), contributing to cardiac remodelling and peripheral vascular disturbances. Several studies have shown raised levels of inflammatory cytokines such as TNF-alpha, IL-1beta and -6 in HF patients in plasma, circulating leukocytes, atherosclerotic lesions, and in the failing myocardium itself. Importantly, this rise in inflammatory mediators does not seem to be accompanied by a corresponding increase in anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta; thus resulting in an inflammatory imbalance in the cytokine network. Traditional cardiovascular drugs have little influence on the cytokine network in HF patients. Results from randomised, placebo-controlled anti-TNF studies suggest lack of effect of such therapy. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'; these studies just underscore the challenges in understanding the complex cytokine network in order to develop effective treatment modalities in HF patients. More general immunmodulating treatments, such as pentoxyfylline, intravenous immunoglobulin, thalidomide and statins, have shown promising results in smaller studies, which need to be confirmed in larger studies with hospitalisations and death as the end points. In addition, further research in this area will have to be more precise in identifying the most important 'actors' in the immunopathogenesis of chronic HF.

Animals↗
PubMed2005

Potential role for immunomodulatory therapy in atherosclerotic plaque stabilisation.

Our understanding of the mechanisms underlying acute coronary syndromes has evolved beyond the view that this syndrome reflects a progressive collection of lipids and cellular debris in the vascular wall. Current evidence has implicated a role for inflammation in the pathogenesis of this process. Thus, inflammatory cytokines may attenuate interstitial collagen synthesis, increase matrix degradation and promote apoptosis in several atheroma-associated cell types, and all these cellular events may enhance plaque vulnerability. Recently, a series of experimental studies have reported the plaque-stabilising effects of immunomodulatory therapy such as chemokine blockade, anti-CD40 ligand and IL-10. It is conceivable that some of these approaches will be tested clinically and, if successful, they could provide novel treatment strategies for atherosclerotic plaque stabilisation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Abnormal interleukin-7 function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins, leading to frequent infections, particularly of the respiratory tract. Frequently, T-cell abnormalities are observed. Interleukin-7 (IL-7) is involved in the homeostasis of lymphocytes, and may be elevated in lymphopenia. Mutations of genes related to IL-7 may lead to severe immunodeficiency disorders. We report elevated plasma levels of circulating IL-7 in a subgroup of CVID. These patients have increased numbers of circulating CD8+ T cells with decreased apoptosis and a predominance of CC chemokine receptor 7- (CCR7-) effector-memory T cells. Moreover, in some of these patients there is impaired response to IL-7 as assessed by in vitro proliferation and secretion of interferon gamma and transforming growth factor beta. These findings suggest novel pathogenic mechanisms and specific targets for further research in CVID.

Adult↗