Andrey Kazakov

Universität des Saarlandes, Saarbrücken, Saarland, Germany

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Publications (21)156.48 Total impact

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    ABSTRACT: Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 08/2015; 22(3). DOI:10.1016/j.cmet.2015.07.008 · 17.57 Impact Factor
  • RA Hall · A Kazakov · U Laufs · M Böhm · F Lammert
    Zeitschrift für Gastroenterologie 01/2015; 53(01). DOI:10.1055/s-0034-1397085 · 1.05 Impact Factor
  • RA Hall · A Kazakov · U Laufs · M Böhm · F Lammert
    Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386098 · 1.05 Impact Factor
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    ABSTRACT: The progression of liver fibrosis in response to chronic injury varies considerably among individual patients. The underlying genetics is highly complex due to large numbers of potential genes, environmental factors and cell types involved. Here, we provide the first toxicogenomic analysis of liver fibrosis induced by carbon tetrachloride in the murine 'genetic reference panel' of recombinant inbred BXD lines. Our aim was to define the core of risk genes and gene interaction networks that control fibrosis progression. Liver fibrosis phenotypes and gene expression profiles were determined in 35 BXD lines. Quantitative trait locus (QTL) analysis identified seven genomic loci influencing fibrosis phenotypes (pQTLs) with genome-wide significance on chromosomes 4, 5, 7, 12, and 17. Stepwise refinement was based on expression QTL mapping with stringent selection criteria, reducing the number of 1,351 candidate genes located in the pQTLs to a final list of 11 cis-regulated genes. Our findings demonstrate that the BXD reference population represents a powerful experimental resource for shortlisting the genes within a regulatory network that determine the liver's vulnerability to chronic injury.
    PLoS ONE 02/2014; 9(2):e89279. DOI:10.1371/journal.pone.0089279 · 3.23 Impact Factor
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    ABSTRACT: The endothelial nitric oxide synthase (eNOS) contributes to cardiac remodelling. We studied the role of eNOS in the development of myocardial fibrosis during cardiac overload.Methods & ResultsTen-week-old male C57/Bl6 wildtype (WT) and eNOS mice (eNOS(-/-)) were subjected to transverse aortic constriction (TAC, 360 µm) and WT were treated with L-N(G)-nitroarginine methyl ester (L-NAME, 100 mg/kg/day) for 35 days. Inhibition of eNOS by L-NAME induced interstitial fibrosis, augmented replacement fibrosis and induced apoptosis of cardiac fibroblasts and cardiomyocytes. L-NAME and eNOS(-/-) markedly increased the fibrosis induced by TAC and enhanced the myocardial prevalence of CXCR4(pos) fibroblasts. Myocardial SDF-1 expression was up-regulated by L-NAME and down-regulated after TAC. Blood pressure lowering by co-treatment with hydralazine (250 mg/L/day) did not reverse the L-NAME effects.In mice transplanted with green fluorescent protein (GFP)(pos) bone marrow, L-NAME increased the percentage of GFP(pos)fibroblasts in the myocardium to 45-70%. Strain-mismatched BMT of eNOS(-/-)-BM increased and of WT-BM decreased the percentage of CXCR4(pos) fibroblasts in all groups. The number of fibrocytes (CD45(pos)collagen I(pos) cells) in the peripheral blood and in the bone marrow was increased both by TAC and L-NAME. L-NAME but not the inhibitor of iNOS 1400W and of nNOS 7-nitroindazole increased hydroxyproline and collagen Iα1. L-NAME up-regulated SDF-1 mRNA in cultured neonatal rat cardiac fibroblasts as well as their migratory capacity. eNOS inhibition induces and enhances cardiac fibrosis independently of blood pressure by activating SDF-1/CXCR4, extracellular matrix production in cardiac fibroblasts and by increasing recruitment of fibrocytes from the bone marrow.
    Cardiovascular Research 07/2013; 100(2). DOI:10.1093/cvr/cvt181 · 5.94 Impact Factor
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    ABSTRACT: AimsIn diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by I(f)-inhibition in this HFPEF-model.Methods and resultsControl mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the I(f)-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure-volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (E(es)) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered E(es) (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 μL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva.Conclusion In db/db, a model of HFPEF, selective HR reduction by I(f)-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, I(f)-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.
    European Heart Journal 07/2012; 34(36). DOI:10.1093/eurheartj/ehs218 · 15.20 Impact Factor
  • R. Hall · A. Kazakov · U. Laufs · M. Böhm · F. Lammert
    Journal of Hepatology 04/2012; 56:S150. DOI:10.1016/S0168-8278(12)60383-3 · 11.34 Impact Factor
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    ABSTRACT: Activation of the receptor for advanced glycation end products by its ligands promotes inflammatory processes and tissue injury. The available evidence suggests that soluble forms of receptor for advanced glycation end products circulating in the plasma may neutralize the ligand-mediated damage by acting as a decoy. Thus, it is hypothesized that receptor for advanced glycation end products expression might be deleterious, whereas soluble receptor for advanced glycation end products might be beneficial in cardiogenic shock. However, until now, no data exist regarding the role of soluble receptor for advanced glycation end products and receptor for advanced glycation end products in humans with cardiogenic shock complicating myocardial infarction. Prospective observational cohort study. Intensive critical care unit of a university hospital. Forty patients with cardiogenic shock complicating acute myocardial infarction, 20 age-matched patients with acute uncomplicated myocardial infarction and, 20 age-matched healthy volunteers. None. Monocytic receptor for advanced glycation end products expression assessed by flow cytometry was significantly increased in cardiogenic shock nonsurvivors (137.02±7.48 mean fluorescence intensity; n=13) compared to survivors (67.80±8.33 mean fluorescence intensity; n=17; p<.001). Conversely, nonsurvivors had significantly decreased plasma soluble receptor for advanced glycation end products levels (79.87±10.62 arbitrary units; n=13; p=.004) compared to survivors (127.65±10.52 arbitrary units; n=17) as assessed by Western blotting. Receptor for advanced glycation end products expression and soluble receptor for advanced glycation end products levels were determined as independent predictors for 28-day mortality in cardiogenic shock confirmed by receiver-operator characteristics and multivariate analysis (receptor for advanced glycation end products: area under the curve, 0.943±0.05; p<.001; soluble receptor for advanced glycation end products: area under the curve, 0.815±0.08; p<.01). Both receptor for advanced glycation end products>103.6 mean fluorescence intensity or soluble receptor for advanced glycation end products<76.88 arbitrary units independently predicted a 27.87-fold (p<.001) and a 3.97-fold (p=.019) increase in 28-day mortality in cardiogenic shock. Enhanced monocytic receptor for advanced glycation end products expression and decreased plasma soluble receptor for advanced glycation end products levels play a central role in patients with cardiogenic shock associated with proinflammatory and destroying pathways, resulting in an enhanced 28-day mortality-rate. Receptor for advanced glycation end products and soluble receptor for advanced glycation end products may be prognostic biomarkers for survival in cardiogenic shock and might represent a novel therapeutic target in cardiogenic shock.
    Critical care medicine 03/2012; 40(5):1513-22. DOI:10.1097/CCM.0b013e318241e536 · 6.31 Impact Factor
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    ABSTRACT: OBJECTIVES: We aimed to characterize different cellular effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 1 (AT1) receptor blockers (ARBs) as mono- or combination therapy in cardiac pressure overload. Methods and RESULTS: C57B1/6 mice received either the ACEI ramipril (2.5 mg/kg body weight), the ARB telmisartan (20 mg/kg body weight), or the combination. In all groups, pressure overload was induced by transverse aortic constriction (TAC). Cardiac hypertrophy (heart weight/tibia length) induced by TAC was reduced in all 3 treatment groups, with the most pronounced effect in the telmisartan group. The cardiomyocyte short-axis diameter and cardiac fibrosis were increased by TAC and similarly reduced by ACEI, ARB, and the combination therapy. The TAC-induced increase in the number of proliferating Ki67(pos) cardiomyocytes and noncardiomyocytes was reduced more potently by ACEI than by ARB. Four days of drug treatment induced a significant increase in Scal(pos)/VEGFR1(pos) endothelial progenitor cells (EPCs) in all animals in the treated SHAM groups. After 1 day of aortic constriction, only ramipril increased EPC numbers; after 5 weeks, telmisartan monotherapy did not change the EPC levels compared to vehicle or the combination therapy but raised it compared to ramipril. Neither TAC nor one of the therapies changed the number of cardiac capillaries per cardiomyocytes. CONCLUSIONS: ACE inhibition and AT1 receptor blockade have beneficial effects in remodeling processes during cardiac pressure overload. There are small differences between the 2 therapeutical approaches, but the combination therapy has no additional benefit.
    Journal of Cardiovascular Pharmacology and Therapeutics 02/2012; 18(1). DOI:10.1177/1074248411434773 · 2.09 Impact Factor
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    ABSTRACT: The endothelial nitric oxide synthase (eNOS) regulates the mobilization and function of endothelial progenitor cells (EPC). We hypothesized that eNOS of the bone marrow (BM) affects cardiac remodelling during myocardial hypertrophy via the regulation of BM-derived vascular progenitor cells. Ten-week-old male C57/Bl6 wild-type (WT) and eNOS mice (eNOS(-/-)) were subjected to transverse aortic constriction (TAC, 360 μm, 35 days) or sham operation inducing cardiac hypertrophy and increasing the numbers of Ki67+ cardiomyocytes in both strains. Myocardial fibrosis was more pronounced in eNOS(-/-) TAC (3.4 ± 0.4 vs. 2.1 ± 0.2% in WT-TAC, P < 0.05). TAC up-regulated the number of EPCs in the peripheral blood and in the BM in WT but not in eNOS(-/-). Baseline migratory capacity of EPCs was lower in eNOS(-/-) and was not raised by TAC in either strain. To test the role of eNOS in the BM during pressure overload, strain-mismatched (WT/eNOS(-/-); eNOS(-/-)/WT) and strain-matched (WT/WT; eNOS(-/-)/eNOS(-/-)) BM transplantations (BMTs) were performed. Cardiac hypertrophy was most pronounced in WT/eNOS(-/-) TAC. Strain-mismatched BMT of eNOS(-/-) BM deteriorated and of WT BM ameliorated cardiac fibrosis, capillary density, the numbers of EPCs in the peripheral blood and in the BM, and their migratory capacity in pressure overload. Following transplantation of green fluorescent protein (GFP)-positive BM, TAC increased the number of BM-derived podocalyxin(pos)GFP(pos) endothelial cells in both strains. eNOS of the BM plays a key role for amelioration of cardiac hypertrophy, capillary density, and fibrosis during increased afterload.
    Cardiovascular Research 11/2011; 93(3):397-405. DOI:10.1093/cvr/cvr305 · 5.94 Impact Factor
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    ABSTRACT: To investigate the role of Toll-like receptor 2 (TLR2) in uncomplicated acute myocardial infarction (AMI) and in cardiogenic shock (CS). In patients with uncomplicated AMI (n = 20), CS (n = 30) and in age-matched healthy controls (HC; n = 20), TLR2 expression on monocytes was assessed by flow cytometry. Tumour necrosis factor alpha (TNFα) and interleukin-6 (IL6) expression in monocytes was analysed by intracellular cytokine staining. TLR2 expression was increased in patients with AMI compared with HC [mean fluorescence intensity (MFI) 111.1 ± 8.2 vs. 66.9 ± 1.5, P < 0.001]. In patients with CS, TLR2 expression was further increased (132.8 ± 5.6 MFI, P = 0.009 vs. AMI). This was accompanied by an increased expression of the proinflammatory cytokines TNFα (4.3 ± 1.6% in AMI vs. 20.5 ± 5.9% in CS, P = 0.004) and IL6 (6.3 ± 1.6% in AMI vs. 20.6 ± 6.2% in CS, P = 0.032). Furthermore, in all patients with myocardial infarction (AMI + CS; n = 50), a strong correlation between the monocytic TLR2 expression and the symptom to reperfusion time (r(2)= 0.706, P < 0.001) was found, implying tissue hypoxia dependency. Symptom to reperfusion time is a main factor to influence TLR2 expression but not the presence of CS. TLR2 expression of mononuclear cells exposed in vitro to hypoxia was assessed by flow cytometry and western blot. In vitro measurements showed a hypoxia-mediated monocytic TLR2 expression up-regulation. We demonstrate TLR2 up-regulation and increased proinflammatory cytokine expression in circulating monocytes in AMI/CS depending on disease severity, implying an important role of TLR2 expression in ischaemic injury.
    European Heart Journal 10/2011; 33(9):1085-94. DOI:10.1093/eurheartj/ehr377 · 15.20 Impact Factor
  • M Lenski · A Kazakov · N Marx · M Böhm · U Laufs
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    ABSTRACT: Type 2 diabetes is associated with an increased risk of cardiac complications. Inhibitors of dipeptidylpeptidase 4 (DPP-4) are novel drugs for the treatment of patients with type 2 diabetes. The effect of DPP-4 inhibitors on myocardial metabolism has not been studied in detail. In wild-type C57Bl6-mice, 3weeks of treatment with sitagliptin had no effect on body weight and glucose tolerance nor on phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoAcarboxylase (ACC), phosphofructokinase-2 (PFK2) or tuberin-2 (TSC2) in the left ventricular myocardium. However, in 10week old db/db-/- mice, a model of diabetes and obesity, sitagliptin potently reduced plasma glucose rise in peritoneal glucose tolerance tests and reduced weight increase. The myocardium of untreated db/db-/- mice exhibited a marked increase of the phosphorylation of AMPK, ACC, TSC2, expression of p53 and fatty acid translocase (FAT/CD36) membrane expression. These changes were reduced by DPP-4 inhibition. Sitagliptin showed no effect on cardiomyocyte size but prevented myocardial fibrosis in the 10week old db/db-/- mice and reduced expression of TGF-β1, markers of oxidative stress and the accumulation of advanced glycation end products in cardiomyocytes. Working heart analyses did not show an effect of sitagliptin on parameters of systolic cardiac function. In animals with diabetes and obesity, sitagliptin improved glucose tolerance, reduced weight gain, myocardial fibrosis and oxidative stress. Furthermore the study provides evidence that treatment with sitagliptin decreases elevated myocardial fatty acid uptake and oxidation in the diabetic heart. These observations show beneficial myocardial metabolic effect of DPP-4 inhibition in this mouse model of diabetes and obesity.
    Journal of Molecular and Cellular Cardiology 08/2011; 51(6):906-18. DOI:10.1016/j.yjmcc.2011.08.001 · 4.66 Impact Factor
  • R Hall · P Müller · U Laufs · M Böhm · F Lammert · A Kazakov
    Zeitschrift für Gastroenterologie 08/2011; 49(08). DOI:10.1055/s-0031-1285725 · 1.05 Impact Factor
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    ABSTRACT: Vascular effects of mental stress are only partially understood. Therefore, we studied effects of chronic stress and heart rate (HR) on endothelial function and cerebral ischemia. 129S6/SvEv mice were randomized to the I(f)-channel inhibitor ivabradine (10 mg/kg per day) or vehicle and underwent a chronic stress protocol for 28 days. Stress increased HR from 514 ± 10 bpm to 570 ± 14 bpm, this was prevented by ivabradine (485 ± 7 bpm). Endothelium-dependent relaxation of aortic rings was impaired in mice exposed to stress. HR reduction restored endothelial function to the level of naive controls. Vascular lipid hydroperoxides were increased to 333% ± 24% and vascular NADPH oxidase activity was upregulated to 223 ± 38% in stressed mice, which was prevented by ivabradine. Stress reduced aortic endothelial nitric oxide synthase mRNA expression to 84% ± 3% and increased AT1 receptor mRNA to 168% ± 18%. Both effects were attenuated by HR reduction. In brain tissue, stress resulted in an upregulation of lipid hydroperoxides to 140% ± 11%, which was attenuated by HR reduction. Ivabradine increased brain capillary density in naive and in stressed mice. Mice exposed to chronic stress before induction of ischemic stroke by transient middle cerebral artery occlusion exhibited increased lesion size (33.7 ± 2.3 mm3 versus 23.9 ± 2.4 mm3). HR reduction led to a marked reduction of the infarct volume to 12.9 ± 3.3 mm3. Chronic stress impairs endothelial function and aggravates ischemic brain injury. HR reduction protects from cerebral ischemia via improvement of endothelial function and reduction of oxidative stress. These results identify heart rate as a mediator of vascular effects induced by chronic stress.
    Stroke 06/2011; 42(6):1742-9. DOI:10.1161/STROKEAHA.110.598607 · 5.72 Impact Factor
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    ABSTRACT: Inosculation of preformed microvessels with the host microvasculature represents a promising approach to accelerate vascularization of tissue constructs. Herein, we analyzed whether cultivation of prevascularized tissue constructs promotes inosculation by reducing the perivascular cell coverage of the preformed microvessels. Poly(ester-urethane) scaffolds were implanted into FVB/N-TgN (Tie2/green fluorescent protein [GFP]) 287 Sato mice to generate prevascularized tissue constructs with GFP-positive microvessels. These constructs were then cultivated for 3 or 10 days before implantation into dorsal skinfold chambers of FVB/N mice to analyze inosculation and vascularization by intravital fluorescence microscopy and immunohistochemistry. Noncultivated tissue constructs served as controls. Cultivation reduced the number of α-smooth muscle actin-positive preformed microvessels within the constructs and increased the production of vascular endothelial growth factor. After 3 days of cultivation, tissue constructs still exhibited good cell viability, whereas apoptotic cell death was massively increased in the 10-day-cultivated group. After implantation, inosculation of preformed microvessels was accelerated in the 3-day-cultivated constructs. This resulted in an improved vascularization, as indicated by an increased functional microvessel density and blood perfusion. Immunohistochemical detection of GFP-positive microvessels revealed that internal and external inosculation occurs in parallel. In conclusion, this study demonstrates that inosculation of in situ prevascularized tissue constructs can be easily accelerated by destabilization of preformed microvessels and angiogenic activation during short-term cultivation.
    Tissue Engineering Part A 10/2010; 17(5-6):841-53. DOI:10.1089/ten.TEA.2010.0329 · 4.64 Impact Factor
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    ABSTRACT: The small GTPase Rac1 seems to play a role in the pathogenesis of atrial fibrillation (AF). The aim of the present study was to characterize the effects of Rac1 overexpression on atrial electrophysiology. In mice with cardiac overexpression of constitutively active Rac1 (RacET), statin-treated RacET, and wild-type controls (age 6 months), conduction in the right and left atrium (RA and LA) was mapped epicardially. The atrial effective refractory period (AERP) was determined and inducibility of atrial arrhythmias was tested. Action potentials were recorded in isolated cells. Left ventricular function was measured by pressure-volume analysis. Five of 11 RacET hearts showed spontaneous or inducible atrial tachyarrhythmias vs. 0 of 9 controls (P < 0.05). In RacET, the P-wave duration was significantly longer (26.8 +/- 2.1 vs. 16.7 +/- 1.1 ms, P = 0.001) as was total atrial activation time (RA: 13.6 +/- 4.4 vs. 3.2 +/- 0.5 ms; LA: 7.1 +/- 1.2 vs. 2.2 +/- 0.3 ms, P < 0.01). Prolonged local conduction times occurred more often in RacET (RA: 24.4 +/- 3.8 vs. 2.7 +/- 2.1%; LA: 19.1 +/- 6.3 vs. 1.2 +/- 0.7%, P < 0.01). The AERP and action potential duration did not differ significantly between both groups. RacET demonstrated significant atrial fibrosis but only moderate systolic heart failure. RacET and statin-treated RacET were not significantly different regarding atrial electrophysiology. The substrate for atrial arrhythmias in mice with Rac1 overexpression is characterized by conduction disturbances and atrial fibrosis. Electrical remodelling (i.e. a shortening of AERP) does not play a role. Statin treatment cannot prevent the structural and electrophysiological effects of pronounced Rac1 overexpression in this model.
    Cardiovascular Research 03/2010; 87(3):485-93. DOI:10.1093/cvr/cvq079 · 5.94 Impact Factor
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    ABSTRACT: Inhibition of the angiotensin-converting enzyme (ACE) prevents maladaptive cardiac remodelling. Endothelial progenitor cells (EPC) from the bone marrow contribute to endothelial repair and neovascularization, effects that are potentially important during cardiac remodelling. We hypothesized that ACE inhibitors may exert beneficial effects during pressure-induced myocardial hypertrophy by regulating progenitor cell function. In C57/Bl6 mice, development of cardiac hypertrophy induced by transaortic constriction (TAC) for 5 weeks was reduced by ramipril, 5 mg/kg p.o., independent of blood pressure lowering. Ramipril prevented TAC-induced apoptosis of cardiac myocytes and endothelial cells. On day 1 after TAC, upregulation of Sca-1(pos)/KDR(pos) EPC was observed, which was further increased by ramipril. EPC were persistently elevated in the TAC mice receiving vehicle treatment but not in the ramipril group after 5 weeks. These effects were independent of hypoxia-inducible factor-1alpha mRNA and protein expression. The ACE inhibitor but not TAC improved the migratory capacity of DiLDL(pos) EPC. Increased cardiac afterload induced upregulation of extracardiac neoangiogenesis. This effect was enhanced by ACE inhibition. Ramipril but not TAC markedly increased cardiac capillary density determined by the ratio of CD31(pos) cells to cardiomyocytes. Bone marrow transplantation studies revealed that TAC increased the percentage of bone marrow-derived GFP(pos) endothelial cells in the myocardium, and ramipril made this effect more pronounced. ACE inhibition prevents pressure-induced maladaptive cardiac hypertrophy and increases intra- and extracardiac neoangiogenesis associated with the upregulation of EPC and amelioration of EPC migration. The regulation of progenitor cells from the bone marrow identifies a novel effect of ACE inhibitors during cardiac remodelling.
    Cardiovascular Research 05/2009; 83(1):106-14. DOI:10.1093/cvr/cvp123 · 5.94 Impact Factor
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    ABSTRACT: The purpose of this study was to study the underlying molecular mechanisms of the protective cardiac effects of physical exercise. Telomere-regulating proteins affect cellular senescence, survival, and regeneration. C57/Bl6 wild-type, endothelial nitric oxide synthase (eNOS)-deficient and telomerase reverse transcriptase (TERT)-deficient mice were randomized to voluntary running or no running wheel conditions (n = 8 to 12 per group). Short-term running (21 days) up-regulated cardiac telomerase activity to >2-fold of sedentary controls, increased protein expression of TERT and telomere repeat binding factor (TRF) 2, and reduced expression of the proapoptotic mediators cell-cycle-checkpoint kinase 2 (Chk2), p53, and p16. Myocardial and leukocyte telomere length did not differ between 3-week- and 6-month-old sedentary or running mice, but telomerase activity, TRF2 and TERT expression were persistently increased after 6 months and the expression of Chk2, p53, and p16 remained down-regulated. The exercise-induced changes were absent in both TERT(-/-) and eNOS(-/-) mice. Running increased cardiac expression of insulin-like growth factor (IGF)-1. Treatment with IGF-1 up-regulated myocardial telomerase activity >14-fold and increased the expression of phosphorylated Akt protein kinase and phosphorylated eNOS. To test the physiologic relevance of these exercise-mediated prosurvival pathways, apoptotic cardiomyopathy was induced by treatment with doxorubicin. Up-regulation of telomere-stabilizing proteins by physical exercise in mice reduced doxorubicin-induced p53 expression and potently prevented cardiomyocyte apoptosis in wild-type, but not in TERT(-/-) mice. Long- and short-term voluntary physical exercise up-regulates cardiac telomere-stabilizing proteins and thereby induces antisenescent and protective effects, for example, to prevent doxorubicin-induced cardiomyopathy. These beneficial cardiac effects are mediated by TERT, eNOS, and IGF-1.
    Journal of the American College of Cardiology 08/2008; 52(6):470-82. DOI:10.1016/j.jacc.2008.04.034 · 16.50 Impact Factor
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    ABSTRACT: The regulation of angiogenesis in the hypertrophied overloaded heart is incompletely understood. Bone-marrow-derived progenitor cells have been shown to contribute to endothelial homeostasis, repair, and new blood vessel formation. We therefore studied the effects of pressure overload on angiogenesis and progenitor cells. Pressure overload induced by transaortic constriction (TAC, C57/Bl6 mice, 360 microm for 35 days) increased left ventricular (LV) systolic pressure, the ratio of heart weight to tibia length, cardiomyocyte diameters, and cardiac apoptosis and fibrosis compared to sham-operated mice. In the TAC group, the number of cycling Ki67 pos cells increased from none to 0.1 +/- 0.02% in cardiomyocytes and from 0.17 +/- 0.02% to 0.65 +/- 0.1% in non-cardiomyocytes, P < 0.001. stem cell antigen 1(pos)/vascular endothelial growth factor receptor 2 pos endothelial progenitor cells (EPC) increased to 210 +/- 25% in the blood and to 196 +/- 21% in the bone marrow (P < 0.01). TAC upregulated cultured spleen-derived DiLDL pos/lectin pos EPC to 221 +/- 37%, P < 0.001. Cardiac hypertrophy and upregulation of EPC secondary to cardiac pressure overload were associated with increased extra-cardiac neoangiogenesis (54 +/- 12% increase, P < 0.05). In endothelial nitric oxide synthase double knockout mice, the upregulation of EPC by TAC was abolished. Maladaptive myocardial remodelling in TAC mice was characterized by a reduction of CD31 pos cells. In mice transplanted with green fluorescent protein pos bone marrow, TAC markedly increased myocardial bone marrow-derived CD31 pos cells from 2.37 +/- 0.4% to 7.76 +/- 1.5% and MEF2 pos cells from 1.8 +/- 0.4/mm2 to 20.5 +/- 5.3/mm2, P < 0.05. Pressure-induced myocardial hypertrophy leads to upregulation of systemic EPCs, increased extra-cardiac angiogenesis, and upregulation of intra-myocardial bone marrow-derived endothelial and myocyte precursor cells. The data show that afterload-dependent regulation of bone marrow-derived progenitor cells contributes to angiogenesis in myocardial hypertrophy.
    Cardiovascular Research 01/2008; 77(1):151-9. DOI:10.1093/cvr/cvm037 · 5.94 Impact Factor
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    Journal of the American College of Cardiology 09/2006; 48(4):843-5. DOI:10.1016/j.jacc.2006.05.037 · 16.50 Impact Factor

Publication Stats

367 Citations
156.48 Total Impact Points


  • 2005–2014
    • Universität des Saarlandes
      • Klinik für Innere Medizin III - Kardiologie, Angiologie und internistische Intensivmedizin
      Saarbrücken, Saarland, Germany
  • 2008–2011
    • Universitätsklinikum des Saarlandes
      Homburg, Saarland, Germany