Awards & achievements
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Sep 2011Award: ESC2011 Young Investigator Award in Thrombosis and Haemostasis
Other
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Languagesrussian, ukrainian, german, english
Publications (35) View all
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Article: Peripheral blood monocyte sirt1 expression is reduced in patients with coronary artery disease.
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ABSTRACT: Inflammation plays a key role in atherosclerosis. Sirt1 regulates transcription factors involved in inflammatory processes and blunts atherosclerosis in mice. However, its role in humans remains to be defined. This study was therefore designed to investigate the role of Sirt1 in the development of atherosclerosis. 48 male subjects admitted for cardiac catheterization were subdivided into healthy subjects, patients with stable coronary artery disease (CAD), and with acute coronary syndromes (ACS). Monocytes were isolated and Sirt1 mRNA levels were determined. Sirt1 gene expression was higher in healthy subjects as compared to patients with CAD or ACS (P<0.05), respectively. Interestingly, HDL levels correlated positively with Sirt1 expression. Thus, HDL from the three groups was isolated and incubated with THP-1 monocytes to determine the effects of HDL on Sirt1 protein in controlled experimental conditions. HDL from healthy subjects stimulated Sirt1 expression in THP-1 monocytes to a higher degree than HDL from CAD and ACS patients (P<0.05). Paraoxonase-1 (PON-1), a HDL-associated enzyme, showed a reduced activity in HDL isolated from CAD and ACS patients as compared to the controls (P<0.001). Monocytic Sirt1 expression is reduced in patients with stable CAD and ACS. Experiments on THP-1 monocytes suggest that this effect is HDL-dependent and is mediated by a reduced activity of HDL-associated enzyme PON1.PLoS ONE 01/2013; 8(1):e53106. · 4.09 Impact Factor -
Article: Inhibition of Nicotinamide Phosphoribosyltransferase Reduces Neutrophil-Mediated Injury in Myocardial Infarction.
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ABSTRACT: Abstract Aims: Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and recent evidence indicates its role in inflammatory processes. Here, we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed. Results: Treatment with FK866 reduced myocardial infarct size, neutrophil infiltration, and reactive oxygen species (ROS) generation within infarcted hearts in vivo in a mouse model of ischemia and reperfusion. The benefit of FK866 was not shown in the Langendorff model (ex vivo model of working heart without circulating leukocytes), suggesting a direct involvement of these cells in cardiac injury. Sera from FK866-treated mice showed reduced circulating levels of the neutrophil chemoattractant CXCL2 and impaired capacity to prime migration of these cells in vitro. The release of CXCL8 (human homolog of murine chemokine CXCL2) by human peripheral blood mononuclear cells (PBMCs) and Jurkat cells was also reduced by FK866, as well as by sirtuin (SIRT) inhibitors and SIRT6 silencing, implying a pivotal role for this NAD(+)-dependent deacetylase in the production of this chemokine. Innovation: The pharmacological inhibition of Nampt might represent an effective approach to reduce neutrophilic inflammation- and oxidative stress-mediated tissue damage in early phases of reperfusion after a myocardial infarction. Conclusions: Nampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice. Antioxid. Redox Signal. 00, 000-000.Antioxidants & Redox Signaling 03/2012; · 8.20 Impact Factor -
Article: Polycyclic aromatic hydrocarbons impair function of β2-adrenergic receptors in airway epithelial and smooth muscle cells.
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ABSTRACT: Incomplete combustion produces a pollutant mixture that includes polycyclic aromatic hydrocarbons (PAHs). Previous work by the Columbia Center for Children's Environmental Health (CCCEH) and others linked exposure to PAH with symptoms of asthma and other adverse health effects in young children. Inhaled β(2)-adrenergic agonists are mainstays in the treatment of reactive airway diseases. These exogenous catecholamines engage membrane-bound β(2)-adrenergic receptors (β(2)AR) on airway epithelial and smooth muscle cells to cause airway dilation. We hypothesized that exposure to PAH might similarly interfere with the function of β(2)AR in airway epithelial or smooth muscle cells, reducing the efficacy of a medication important for the treatment of asthma symptoms. A PAH mixture was devised, based on ambient levels measured prenatally among a cohort of pregnant women participating at the CCCEH. Primary airway epithelial and smooth muscle cells were exposed to varying concentrations of the PAH mixture, and expression, function, and signaling of β(2)AR were assessed. Murine tracheal epithelial cells and human airway smooth muscle cells, after exposure to a PAH mixture, exhibited reduced expression and function of β(2)AR. These findings support our hypothesis that environmentally relevant PAHs can impede β(2)AR-mediated airway relaxation, and suggest a new paradigm where air pollutants not only contribute to the pathogenesis of childhood asthma, but also diminish responsiveness to standard therapy.American Journal of Respiratory Cell and Molecular Biology 05/2011; 45(5):1045-9. · 5.13 Impact Factor -
Article: PDGF-CC induces tissue factor expression: role of PDGF receptor alpha/beta.
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ABSTRACT: Tissue factor (TF) is the principal trigger of the coagulation cascade and involved in arterial thrombus formation. Platelet-derived growth factor CC (PDGF-CC) is a recently discovered member of the PDGF family released upon platelet activation. This study assesses the impact of PDGF-CC on TF expression in human cells. PDGF-CC concentration-dependently induced TF expression by 2.5-fold in THP-1 cells, by 2.0-fold in human peripheral blood monocytes, by 1.4-fold in vascular smooth muscle cells, and by 2.6-fold in microvascular endothelial cells, but did not affect TF expression in aortic endothelial cells. A similar pattern was observed with PDGF-BB. In contrast, PDGF-AA did not alter TF expression in THP-1 cells. TF whole cell activity was induced following stimulation with PDGF-BB and PDGF-CC in THP-1 cells. Real-time polymerase chain reaction revealed that PDGF-CC induced TF mRNA. PDGF-CC transiently activated p42/44 MAP kinase [extracellular signal-regulated kinase (ERK)], while phosphorylation of the MAP kinases c-Jun NH(2)-terminal kinase (JNK) and p38 remained unaffected. PD98059, a specific inhibitor of ERK phosphorylation, but not the p38 inhibitor SB203580 or the JNK inhibitor SP600125 prevented PDGF-CC induced TF expression in a concentration-dependent manner. The effect of PDGF-CC was antagonized by both PDGF receptor alpha and PDGF receptor beta neutralizing antibodies; in contrast, PDGF-BB was only inhibited by PDGF receptor beta blocking antibody. PDGF receptor alpha and PDGF receptor beta inhibition prevented PDGF-CC-induced ERK phosphorylation. PDGF-CC induces TF expression via activation of alpha/beta receptor heterodimers and an ERK-dependent signal transduction pathway.Archiv für Kreislaufforschung 10/2009; 105(3):349-56. · 7.35 Impact Factor -
Article: Laminin receptor activation inhibits endothelial tissue factor expression.
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ABSTRACT: Tissue factor (TF) is an important trigger of arterial thrombosis. The green tea catechin epigallocatechin-3-gallate (EGCG) is a ligand of the 67-kDa laminin receptor (67LR) and exhibits cardioprotective effects. This study investigates whether 67LR regulates TF expression in human endothelial cells. Immunofluorescence demonstrated that human aortic endothelial cells expressed 67LR. Cells grown on laminin expressed 35% less TF in response to TNF-alpha (TNF-alpha) than those grown on fibronectin (n=6; p<0.001). EGCG (1-30 microM) inhibited TNF-alpha and histamine induced endothelial TF expression and activity in a concentration dependent manner resulting in 87% reduction of TF expression (n=5; p<0.001); in contrast, expression of tissue factor pathway inhibitor was not affected (n=4; p=NS). In vivo administration of EGCG (30 mg/kg/day) inhibited TF activity in carotid arteries of C57BL6 mice. Real-time PCR and promoter studies revealed that EGCG decreased TF expression at the transcriptional level and impaired activation of the mitogen activated protein (MAP) kinase JNK 1/2, but not ERK or p38. Similarly, the JNK 1/2 inhibitor SP600125 (1 microM) impaired TF promoter activity (n=4; p<0.001) and protein expression (n=4; p<0.001). 67LR blocking antibodies blunted the inhibitory effect of EGCG on both TF protein expression and JNK activation. In contrast, vascular cell adhesion molecule 1 (VCAM-1) was not affected by laminin nor EGCG, and its expression was not regulated by JNK. EGCG did not affect TNF-alpha stimulated NFkB activation. Laminin receptor activation inhibits endothelial TF expression by impairing JNK phosphorylation. Thus, 67LR may be a potential target for the development of novel anti-thrombotic therapies.Journal of Molecular and Cellular Cardiology 09/2009; 48(6):1138-45. · 5.17 Impact Factor
