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Khurrum Shahzad,
Madhusudhan Thati,
Hongjie Wang,
Muhammed Kashif,
Juliane Wolter,
Satish Ranjan,
Tao He,
Qianxing Zhou, Erwin Blessing,
Angelika Bierhaus,
Peter P Nawroth,
Berend Isermann
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ABSTRACT: Minocycline, a tetracycline derivate, mediates vasculoprotective effects independent of its antimicrobial properties. Thus, minocycline protects against diabetic nephropathy and reduces neointima formation following vascular injury through inhibition of apoptosis or migration, respectively. Whether minocycline has an effect on primary atherogenesis remains unknown.
Using morphological and immunohistochemical analyses we determined de novo atherogenesis in ApoE-/- mice receiving a high fat diet (HFD) with or without minocycline treatment. The effect of minocycline on proliferation, expression of p27(Kip1) or PARP-1 (Poly [ADP-ribose] polymerase 1), or on PAR (poly ADP-ribosylation) modification in vascular smooth muscle cells (VSMC) was analyzed in ex vivo and in vitro (primary human and mouse VSMC).
Minocycline reduced plaque size and stenosis in ApoE-/- HFD mice. This was associated with a lower number and less proliferation of VSMC, reduced PAR (poly ADP-ribosylation) modification and increased p27(Kip1) expression within the plaques. In agreement with the ex vivo data minocycline reduced proliferation, PARP-1 expression, PAR modification while inducing p27 expression in human and mouse VSMC in vitro. These effects were observed at a low minocycline concentration (10 μM), which had no effect on VSMC migration or apoptosis. Minocycline inhibited PARP-1 and induced p27(Kip1) expression in VSMC as efficiently as the specific PARP-1 inhibitor PJ 34. Knock down of p27(Kip1) abolished the antiproliferative effect of minocycline. These data establish a novel antiatherosclerotic mechanism of minocycline during de novo atherogenesis, which depends on p27(Kip1) mediated inhibition of VSMC proliferation.
Atherosclerosis 06/2011; 219(1):74-83. · 3.79 Impact Factor
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ABSTRACT: The multiligand receptor for advanced glycation end products (RAGE) of the immunoglobulin superfamily is expressed on multiple cell types implicated in the inflammatory response in atherosclerosis. We sought to determine the role of bone marrow-derived RAGE in different stages of atherosclerotic development in apolipoprotein E-deficient mice (apoE(-/-)).
Seven- and 23-week-old apoE(-/-) mice (n = 40) were lethally irradiated and given bone marrow from RAGE null (RAGE(-/-)/apoE(-/-)) or RAGE-bearing (RAGE(+/+)/apoE(-/-)) mice to apoE(-/-) mice to generate double knockout bone marrow chimera (RAGE(-/-)/apoE(-/-bmc) and RAGE(+/+)/apoE(-/-bmc)-, respectively). After 16 weeks on a standard chow diet, mice were sacrificed and atherosclerotic lesion formation was evaluated.
Plaques in the aortic root of the young mice showed no significant difference in maximum plaque size (217,470 ± 17,480 μm(2) for the RAGE(-/-) /apoE(-/-bmc) mice compared to 244,764 ± 45,840 μm(2)), whereas lesions in the brachiocephalic arteries of the older RAGE(-/-)/apoE(-/-bmc) mice had significantly smaller lesions (94,049 ± 13,0844 μm(2) vs. 145,570 ± 11,488 μm(2), P < 0.05) as well as reduced average necrotic core area (48,600 ± 9220 μm(2) compared to 89,502 ± 10,032 μm(2), P < 0.05) when compared to RAGE(+/+)/apoE(-/-bmc) mice. Reduced plaque size and more stable plaque morphology was associated with significant reduced expression of VCAM-1, ICAM-1 and MCP-1. Accumulation of the RAGE ligand HMGB-1 was also significantly reduced within the lesions of RAGE(-/-)/apoE(-/-bmc) mice.
This study demonstrates that bone marrow-derived RAGE is an important factor in the progression of atherosclerotic plaques.
European Journal of Clinical Investigation 03/2011; 41(11):1164-71. · 3.02 Impact Factor
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ABSTRACT: Inflammation contributes to atherosclerotic plaque initiation and progression. Recent studies suggest that nicotinic acid has anti-inflammatory effects independent of its lipid-modifying capabilities. We assessed the hypothesis that administration of nicotinic acid to older apolipoprotein E (apoE)-deficient mice with established lesions will reduce lesion size and plaque inflammation independent of its lipid-modifying effects. Therefore nicotinic acid was administered to 27-week-old apo E-deficient mice exhibiting advanced atherosclerotic lesions within the innominate artery. After 27 weeks of treatment both animal groups had no significant changes in plasma lipid levels. Mice treated with nicotinic acid (n = 22) demonstrated a 30% reduction in total lesion area compared with controls (n = 20). Furthermore, they revealed a more stable plaque composition with an increase in fibrous cap thickness and a reduction in the size of the necrotic core. Immunohistochemistry demonstrated a reduced accumulation of macrophages and a reduced expression of vascular cell adhesion molecule-1 and tissue factor. Additionally, administration of nicotinic acid significantly reduced tumor necrosis factor alpha expression in the thoracic aorta as demonstrated by real-time PCR. In conclusion, these data suggest that long-term administration of nicotinic acid has anti-atherogenic and anti-inflammatory properties on advanced atherosclerotic lesions, which are independent of its lipid-modifying actions.
Journal of cardiovascular pharmacology 01/2011; 57(4):447-54. · 2.83 Impact Factor
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ABSTRACT: Thrombin not only plays a central role in thrombus formation and platelet activation, but also in induction of inflammatory processes. Activated factor X (FXa) is traditionally known as an important player in the coagulation cascade responsible for thrombin generation. We assessed the hypothesis that rivaroxaban, a direct FXa inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions in an in vivo model.
Rivaroxaban (1 or 5 mg/kg body weight/day) or standard chow diet was administered for 26 weeks to apolipoprotein E-deficient mice (n = 20 per group) with already established atherosclerotic lesions. There was a nonsignificant reduction of lesion progression in the high-concentration group, compared to control mice. FXa inhibition with 5 mg Rivaroxaban/kg/day resulted in increased thickness of the protective fibrous caps (12.3 ± 3.8 μm versus 10.1 ± 2.7 μm; P < .05), as well as in fewer medial erosions and fewer lateral xanthomas, indicating plaque stabilizing properties. Real time-PCR from thoracic aortas revealed that rivaroxaban (5 mg/kg/day) treatment reduced mRNA expression of inflammatory mediators, such of IL-6, TNF-α, MCP-1, and Egr-1 (P < .05).
Chronic administration of rivaroxaban does not affect lesion progression but downregulates expression of inflammatory mediators and promotes lesion stability in apolipoprotein E-deficient mice.
Mediators of Inflammation 01/2011; 2011:432080. · 3.26 Impact Factor
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ABSTRACT: The acute phase response to Chlamydia pneumoniae infection was analyzed over a 72 h period post-infection in C57BL/6J mice. A single intra-nasal inoculation stimulated statistically significant increases in the plasma levels of IL-2, IL-5, IL-6, IL-10, IL-12, GM-CSF, IFN-gamma, and serum amyloid A but not TNF-alpha, IL-1beta, IL-4 and serum amyloid P. There was also a decrease in the activity of the HDL protective enzyme paraoxonase as well as a reduced ability of HDL to prevent oxidation of palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine by hydroperoxyoctadecadienoic acid at 48 and 72 h post-infection. To determine whether the C. pneumoniae induced acute phase response had any effect on atherosclerotic plaque stability, we measured the frequency of intra-plaque hemorrhage as a marker of plaque disruption in the innominate arteries of apolipoprotein E deficient mice at 29-30 weeks and 1.5-2.0 years of age. There was an increased frequency of intra-plaque hemorrhage only in the older mice infected with the live organism (8/14) as compared to mice treated with killed C. pneumoniae (2/11) or sham inoculated with PBS (2/12). These results suggest that acute phase reactant proteins produced in response to pulmonary infection with C. pneumoniae may contribute to the progression and destabilization of atherosclerotic lesions.
Microbes and Infection 08/2010; 12(8-9):598-606. · 3.10 Impact Factor
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ABSTRACT: Early growth response gene-1 (Egr-1) regulates the expression of genes important to cardiovascular disease. Within atherosclerotic lesions, Egr-1 is expressed in smooth muscle cells, endothelial cells, and macrophages. Since macrophages play a pivotal role in atherosclerotic lesion initiation and progression, this study investigated the effects of Egr-1 deficiency within bone marrow-derived cells on the development of atherosclerosis in a hyperlipidaemic mouse model.
Bone marrow from Egr-1-deficient mice and wild-type controls was transplanted into lethally irradiated LDL receptor null mice. After 26 weeks on a high fat diet, atherosclerotic lesion size within the aortic sinus of recipients was evaluated. Mice receiving Egr-1-deficient bone marrow had significantly decreased lesion size compared with controls. Lesions of these mice contained fewer macrophages and had reduced expression of vascular cell adhesion molecule-1 (VCAM-1), tissue factor, as well as transforming growth factor receptor type II, which are target genes of Egr-1. These results were validated by in vitro analysis of Egr-1-deficient peritoneal macrophages which, after lipopolysaccharide stimulation, had decreased VCAM-1 and tissue factor mRNA expression compared with wild-type controls.
This study demonstrates that bone marrow-derived Egr-1 promotes macrophage accumulation, atherosclerotic lesion development, and lesion complexity.
Cardiovascular research 05/2010; 86(2):321-9. · 5.80 Impact Factor
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Andrew Remppis,
Florian Bea,
Henry Johannes Greten,
Annette Buttler,
Hongjie Wang,
Qianxing Zhou,
Michael R Preusch,
Ronny Enk,
Robert Ehehalt,
Hugo Katus, Erwin Blessing
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ABSTRACT: The Chinese extract Rhizoma coptidis is well known for its anti-inflammatory, antioxidative, antiviral, and antimicrobial activity. The exact mechanisms of action are not fully understood.
We examined the effect of the extract and its main compound, berberine, on LPS-induced inflammatory activity in a murine macrophage cell line. RAW 264.7 cells were stimulated with LPS and incubated with either Rhizoma coptidis extract or berberine. Activation of AP-1 and NFkappaB was analyzed in nuclear extracts, secretion of MCP-1/CCL2 was measured in supernatants.
Incubation with Rhizoma coptidis and berberine strongly inhibited LPS-induced monocyte chemoattractant protein (MCP)-1 production in RAW cells. Activation of the transcription factors AP-1 and NFkappaB was inhibited by Rhizoma coptidis in a dose- and time-dependent fashion.
Rhizoma coptidis extract inhibits LPS-induced MCP-1/CCL2 production in vitro via an AP-1 and NFkappaB-dependent pathway. Anti-inflammatory action of the extract is mediated mainly by its alkaloid compound berberine.
Mediators of Inflammation 01/2010; 2010:194896. · 3.26 Impact Factor
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Stefanie Seehaus,
Khurrum Shahzad,
Muhammed Kashif,
Ilya A Vinnikov,
Martin Schiller,
Hongjie Wang,
Thati Madhusudhan,
Volker Eckstein,
Angelika Bierhaus,
Florian Bea, Erwin Blessing,
Hartmut Weiler,
David Frommhold,
Peter P Nawroth,
Berend Isermann
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ABSTRACT: Clinical studies failed to provide clear evidence for a proatherogenic role of hypercoagulability. This is in contrast to the well-established detrimental role of hypercoagulability and thrombin during acute atherosclerotic complications. These seemingly opposing data suggest that hypercoagulability might exert both proatherogenic and antiatherogenic effects. We therefore investigated whether hypercoagulability mediates a beneficial effect during de novo atherogenesis.
De novo atherogenesis was evaluated in 2 mouse models with hyperlipidemia and genetically imposed hypercoagulability (TM(Pro/Pro)ApoE(-/-) and FVL(Q/Q)ApoE(-/-) mice). In both mouse models, hypercoagulability resulted in larger plaques, but vascular stenosis was not enhanced secondary to positive vascular remodeling. Importantly, plaque stability was increased in hypercoagulable mice with less necrotic cores, more extracellular matrix, more smooth muscle cells, and fewer macrophages. Long-term anticoagulation reversed these changes. The reduced frequency of intraplaque macrophages in hypercoagulable mice is explained by an inhibitory role of thrombin and protease-activated receptor-1 on monocyte transendothelial migration in vitro. This is dependent on phospholipase-Cbeta, phosphoinositide 3-kinase, and nitric oxide signaling in monocytes but not in endothelial cells.
Here, we show a new function of the coagulation system, averting stenosis and plaque destabilization during de novo atherogenesis. The in vivo and in vitro data establish that thrombin-induced signaling via protease-activated receptor-1, phospholipase-Cbeta, phosphoinositide 3-kinase, and nitric oxide in monocytes impairs monocyte transendothelial migration. This likely accounts for the reduced macrophage accumulation in plaques of hypercoagulable mice. Thus, in contrast to their role in unstable plaques or after vascular injury, hypercoagulability and thrombin convey a protective effect during de novo atherogenesis.
Circulation 09/2009; 120(9):774-84. · 14.74 Impact Factor
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Erwin Blessing
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ABSTRACT: Secondary prevention in patients with coronary heart disease includes treatment with platelet inhibitors, beta-blockers, ACE inhibitors or AT (1)-blockers, and statins. Initiation of therapy generally does not require a slow gradual dose increase. In treatment naive patients with acute coronary syndromes, administration of a loading dose of aspirin and/or clopidogrel is recommended. To reduce flushing, nicotinic acid should be initiated at low stepwise increasing dosages. beta-blocker therapy should not be stopped acutely in coronary heart disease patients. If beta-blocker therapy has to be terminated, blood pressure should be monitored closely and, if necessary controlled with other medication. Termination of statin therapy in the acute phase after strokes or acute coronary syndromes is associated with increased cardiovascular events and should therefore be avoided.
Therapeutische Umschau 11/2008; 65(10):593-7.
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Michael R Preusch,
Marcello Rattazzi,
Claudia Albrecht,
Uta Merle,
Jan Tuckermann,
Günther Schütz, Erwin Blessing,
Giacomo Zoppellaro,
Paolo Pauletto,
Robert Krempien,
Michael E Rosenfeld,
Hugo A Katus,
Florian Bea
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ABSTRACT: Macrophage-derived products are known to play a crucial role during atherogenesis and vascular calcification. Glucocorticoids (GC) are important modulators of immune cell functions, but their specific effects on macrophages behavior during plaque formation are not defined. The present study was therefore designed to investigate the effects of macrophage-specific deletion of the glucocorticoid receptor (GR(LysMCre)) on atherogenesis and vascular calcification in a hyperlipidemic mouse-model.
Bone marrow was isolated from GR(LysMCre) mice and wild-type controls (GR(flox)) and subsequently transplanted into lethally irradiated LDL-receptor-deficient mice. Animals were fed a Western-type diet for 15 or 24 weeks, and atherosclerotic lesions within the aortic sinus were evaluated. At both time points, no significant difference in serum lipid and corticosterone concentrations, atherosclerotic lesion size and macrophage-content within the lesions could be observed. However, GR(LysMCre) mice showed less calcification as well as a significant reduction of RANKL, BMP2, and Msx2 expression within the vasculature. In vitro studies using conditioned media from macrophages which had been stimulated with dexamethasone demonstrated a dose-dependent increase in calcium deposition by vascular smooth muscle cells.
This study demonstrates that macrophage-specific glucocorticoid receptor inactivation reduces vascular calcification without affecting atherosclerotic lesion size in LDL receptor-deficient mice.
Arteriosclerosis Thrombosis and Vascular Biology 10/2008; 28(12):2158-64. · 6.37 Impact Factor
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ABSTRACT: Hyperhomocysteinemia is an independent risk factor for atherosclerosis. Uptake of homocysteine induces oxidative stress in macrophages. Antioxidant response elements (AREs) are regulatory elements within promoters of genes, which protect cells against oxidative stress. The current study investigated whether homocysteine induces transcription of glutamate-cysteine ligase (Gcl), via ARE driven gene expression in mouse macrophages. Gcl is the rate-limiting enzyme in the synthesis of glutathione, an important endogenous antioxidant. Gcl is heterodimeric and the genes encoding the subunits of Gcl contain several AREs within their 5'-promoter regions. Treatment of mouse macrophages with d-/l-homocysteine (50microM) induced depletion of intracellular glutathione and a compensatory increase in Gcl activity. Electro mobiliy shift assays demonstrated increased binding of nuclear proteins to ARE-containing oligonucleotides. Real-time RT-PCR revealed increased mRNA-expression of the catalytic subunit of Gcl (Gclc) after treatment with homocysteine, and this occurred via increased transcription as demonstrated with luciferase promoter reporter constructs for Gclc. Additional site directed mutagenesis demonstrated that ARE4 plays a direct role in mediating induction of Gclc by homocysteine. Supershift analysis and Western blotting revealed that Nrf2 signalling is critical in homocysteine-induced activation of ARE4. Inhibition of MAP kinase activity reduced binding of nuclear proteins to the AREs, nuclear expression of Nrf2 and mRNA expression of Gclc. Western blotting demonstrated phosporylation of ERK1/2 in homocysteine treated macrophages. These data suggest that ARE-driven gene expression of Gclc via a MEK/Nrf2 pathway could help to protect macrophages from oxidative stress due to hyperhomocysteinemia.
Atherosclerosis 08/2008; 203(1):105-11. · 3.79 Impact Factor
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ABSTRACT: Hyperlipidemia is an important complication after organ transplantation and may contribute to the development of posttransplant-accelerated coronary artery disease. Immunosuppressive therapy, especially mammalian target of rapamycin inhibitors, induces a considerable increase in cholesterol and triglyceride plasma levels. Omega-3 fatty acids (FAs) exert cardioprotective effects supporting a therapeutic role in cardiovascular conditions.
An observational study of omega-3 FAs 4 g/day was performed in 15 heart transplant recipients with hypertriglyceridemia. Six patients received rapamycin, and nine received everolimus. Apart from one patient the immunosuppressive therapy was combined with mycophenolate mofetil, only one patient received steroids; two patients presented with diabetes.
Mean triglyceride levels before heart transplantation (HTx) were 137+/-54 mg/dL. After HTx, before sirolimus or everolimus treatment triglyceride level had increased to 188+/-67 mg/dL (P<0.05). Treatment with sirolimus or everolimus induced an increase in triglycerides to 354+/-107 mg/dL (P<0.001). Subsequent treatment with omega-3 FAs for 4 months resulted in a marked decrease in triglycerides to 226+/-74 mg/dL (P<0.001). All patients (100%) showed a reduction in triglyceride by more than 20% (responders). In 10 of 15 patients available 12-month data confirmed the long-term efficacy of omega-3 FAs treatment. There were no adverse events or any discontinuations; no changes in immunosuppression were required.
Treatment with mammalian target of rapamycin inhibitors after HTx induces marked increase in serum levels of triglycerides. Omega-3 FAs significantly lower triglyceride levels and seem to be effective, safe, and well-tolerated in sirolimus- or everolimus-treated heart transplant recipients.
Transplantation 07/2008; 86(2):245-50. · 4.00 Impact Factor
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ABSTRACT: We investigated tolerability and efficacy of ezetimibe treatment (10 mg/d) in 25 heart allograft recipients already on stable statin therapy. Total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C), triglycerides (TG), immunosuppressant drug levels, laboratory and clinical parameters were assessed before, four months and one yr after initiation of ezetimibe treatment. Mean equivalent statin dose was 53.5 +/- 12.3 mg of pravastatin, remaining unchanged throughout the study period. Ezetimibe was generally well tolerated, only two patients (8%) discontinued ezetimibe due to stomach pain or headache. Mean TC decreased from 231.8 +/- 6.4 mg/dL before therapy to 202.2 +/- 8.8 mg/dL after four months and 192.9 +/- 7.0 mg/dL after one yr (p < 0.001). Mean LDL-C decreased from 143.1 +/- 5.4 mg/dL to 121.4 +/- 7.9 mg/dL (month 4; p < 0.05) and 107.1 +/- 5.6 mg/dL (one yr; p < 0.001). TG decreased from 182 +/- 14.3 mg/dL to 173.3 +/- 17.5 mg/dL after one yr (p < 0.05), whereas HDL-C was unchanged. Initial LDL-C and cardiac diagnosis before transplantation were identified as predictors of absolute LDL-C reduction. Immunosuppressant drug doses and blood concentrations were unchanged as well as other laboratory and clinical parameters. Ezetimibe appears safe and effective for further reduction of TC and LDL-C in heart allograft recipients already on stable statin therapy. Extent of pre-treatment LDL-C and cardiac disorder prior to transplantation appear to correlate with the efficacy of ezetimibe therapy.
Clinical Transplantation 05/2008; 22(5):639-44. · 1.67 Impact Factor
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Erwin Blessing,
Michael Preusch,
Roger Kranzhöfer,
Ralf Kinscherf,
Nikolaus Marx,
Michael E Rosenfeld,
Berend Isermann,
Christian M Weber,
Jörg Kreuzer,
Julia Gräfe,
Hugo A Katus,
Florian Bea
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ABSTRACT: Clinical studies have demonstrated that the inhibition of the renin-angiotensin system (RAS) by either an angiotensin-converting enzyme (ACE)-inhibitor or an angiotensin II receptor type 1 (AT(1))-antagonist reduces cardiovascular disease. The objective of this study was to evaluate underlying mechanisms of the AT(1)-antagonist telmisartan in comparison to the ACE-inhibitor ramipril on advanced atherosclerotic lesions. Thirty-two-week-old apolipoprotein E deficient mice (n=60) exhibiting advanced atherosclerotic lesions were fed a chow diet supplemented with ramipril or telmisartan for 16 weeks. Twenty mice received a standard diet. Mice receiving telmisartan had a 38% and mice receiving ramipril had a 18% reduction in progression of atherosclerotic lesion size within the innominate artery. Signs of plaque instability such as frequency of intra-plaque hemorrhage and size of the necrotic cores were reduced in mice receiving telmisartan. Furthermore, telmisartan-treated mice had fewer macrophages and reduced expression of early growth response gene-1 (Egr-1) within the lesions. Electrophoretic mobility shift assays revealed reduced DNA-binding activity of nuclear factor kappaB (NFkappaB) in the aorta of telmisartan-treated mice. In vitro studies in mouse macrophages demonstrated enhanced promoter activation of the nuclear transcription factor peroxisome proliferators-activated receptor gamma (PPARgamma). Target genes of PPARgamma, such as inducible nitric oxide synthase, NFkappaB and Egr-1, showed reduced activity after telmisartan pretreatment. These data suggest that chronic inhibition of the RAS by telmisartan prevails in reducing advanced atherosclerosis and promoting plaque stability over ramipril, possibly through the reduced activity of the pro-inflammatory transcription factors NFkappaB and Egr-1 and through the activation of PPARgamma.
Atherosclerosis 01/2008; 199(2):295-303. · 3.79 Impact Factor
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ABSTRACT: Resident immune cells are a hallmark of atherosclerotic lesions. The sphingolipid analogue drug FTY720 mediates retrafficking of immune cells and inhibits their homing to inflammatory sites. We have evaluated the effect of FTY720 on atherogenesis and lipid metabolism.
ApoE-/- mice on a normal laboratory diet received oral FTY720 for 12 weeks, which led to a 2.4-fold increase in serum cholesterol (largely VLDL fraction) and a 1.8-fold increase in hepatic HMGCoA reductase mRNA. FTY720 increased plasma sphingosine-1-phosphate and induced marked peripheral blood lymphopenia. A discoordinate modulation of B, T and monocyte cell numbers was found in peripheral lymphoid organs. Overall depletion of T cells was accompanied by a relative (2-fold) increase in regulatory T cell content paralleled by a similar increase in effector memory T cells (CD4+ CD44hi CD62lo) as absolute numbers of both subpopulations remained essentially unchanged. Lymphocyte function was unaltered as indicated by anti-OxLDL antibodies and T cell proliferation. There were no changes in atherosclerotic lesions in early and established atherosclerosis.
FTY720 mediated peripheral lymphocyte depletion and retrafficking without altering function and overall balance of pro- and antiatherogenic lymphocyte populations. A net decrease in lymphocyte numbers occurred concomitantly with a more proatherogenic hypercholesterolemia resulting in unaltered atherogenesis.
Arteriosclerosis Thrombosis and Vascular Biology 12/2007; 27(11):2392-9. · 6.37 Impact Factor
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Berend Isermann,
Ilya A Vinnikov,
Thati Madhusudhan,
Stefanie Herzog,
Muhammed Kashif,
Janusch Blautzik,
Marcus A F Corat,
Martin Zeier, Erwin Blessing,
Jun Oh,
Bruce Gerlitz,
David T Berg,
Brian W Grinnell,
Triantafyllos Chavakis,
Charles T Esmon,
Hartmut Weiler,
Angelika Bierhaus,
Peter P Nawroth
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ABSTRACT: Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin-dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy.
Nature Medicine 12/2007; 13(11):1349-58. · 22.46 Impact Factor
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ABSTRACT: Inflammatory mechanisms are involved in initiation and progression of atherosclerotic lesions. Previous studies demonstrated antiinflammatory and consecutive antiatherosclerotic effects of the adenosine analogue 3-Deazaadenosine (c(3) Ado) on early lesion development. The present study evaluated the effect of long-term administration of c(3) Ado in a mouse model of advanced atherosclerosis. Apolipoprotein E-deficient mice (age, 35 weeks; n = 31) with already established advanced atherosclerotic lesions were fed either a diet supplemented with c Ado or a regular chow diet for 21 weeks. Treatment resulted in a significant reduction of serum homocysteine levels. Lesion size and lesion morphology, such as frequency of intraplaque hemorrhage, size of necrotic cores, thickness of fibrous caps, and macrophage content within the plaque, were not different between the groups. Lesion calcification, expression of alpha-actin, and intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1, were inhibited by treatment with c(3) Ado. We could not detect any effect on serum concentrations of interleukin-10 (IL-10) and interleukin-1beta (IL-1beta) or on soluble adhesion molecules intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Electromobility shift assays of protein extracts isolated from aortas did not demonstrate different binding activities of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) after treatment with c Ado. Long-term treatment with the adenosine analogue 3-Deazaadenosine did not show significant effects on progression and stability of advanced atherosclerotic lesions in older apolipoprotein E-deficient mice. A potential antiatherosclerotic effect of c(3)Ado (eg, mediated through inhibition of adhesion molecules) might therefore be limited to prevention of early lesion formation and does not seem to play a relevant role in modifying advanced atherosclerotic disease.
Journal of Cardiovascular Pharmacology 09/2007; 50(2):206-12. · 2.29 Impact Factor
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ABSTRACT: Apical ballooning syndrome, or takotsubo cardiomyopathy, is a syndrome characterized by transient left ventricular dysfunction, frequently presenting with electrocardiographic changes and elevated cardiac biomarkers in the absence of obstructive coronary artery disease. We describe a case where repeated emotional stress caused recurrent ventricular dysfunction in varying regions of the left ventricle.
Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography 04/2007; 20(4):439.e11-2. · 2.98 Impact Factor
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ABSTRACT: Inflammatory mechanisms are involved in atherosclerotic plaque rupture and subsequent thrombin formation. Thrombin not only plays a central role in thrombus formation and platelet activation, but also in the induction of inflammatory processes. We assessed the hypothesis that melagatran, a direct thrombin inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions.
Melagatran (500 micromol/kg/d) or control diet was administered to apolipoprotein E-deficient mice (n=54) with advanced atherosclerotic lesions. Treatment reduced lesion progression in brachiocephalic arteries (P<0.005). Morphometric analysis confirmed that thrombin inhibition promoted plaque stability and resulted in thicker fibrous caps (28.4+/-14.2 microm versus 20.8+/-12.0 microm; P<0.05), increased media thickness (29.3+/-9.6 microm versus 24.4+/-6.7 microm; P<0.05), and smaller necrotic cores (73,537+/-41,301 microm2 versus 126,819+/-51,730 microm2; P<0.0005). Electro mobility shift assays revealed reduced binding activity of nuclear factor kappaB (P<0.05) and activator protein-1 (P<0.05) in aortas of treated mice. Furthermore, immunohistochemistry demonstrated reduced staining for matrix metalloproteinase (MMP)-9 (P<0.05). Melagatran had no significant effect on early lesion formation in C57BL/6J mice.
The direct thrombin inhibitor melagatran reduces lesion size and may promote plaque stability in apolipoprotein E-deficient mice, possibly through reduced activation of proinflammatory transcription factors and reduced synthesis of MMP-9.
Arteriosclerosis Thrombosis and Vascular Biology 12/2006; 26(12):2787-92. · 6.37 Impact Factor
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Motohiro Kamimura,
Christiane Viedt,
Alexander Dalpke,
Michael E Rosenfeld,
Nigel Mackman,
David M Cohen, Erwin Blessing,
Michael Preusch,
Christian M Weber,
Jörg Kreuzer,
Hugo A Katus,
Florian Bea
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ABSTRACT: Atherosclerosis is considered to be an inflammatory disease. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play an essential role in thrombus formation after atherosclerotic plaque rupture. Recent studies suggest that the antiinflammatory cytokine interleukin-10 (IL-10) has many antiatherosclerotic properties. Therefore, the effects of IL-10 on TF expression in response to inflammation were investigated. Mouse macrophages were stimulated with lipopolysaccharide (LPS) in the presence or absence of IL-10. Pretreatment with IL-10 resulted in a 50% decrease in TF mRNA expression and TF promoter activity. Binding of early growth response gene-1 (Egr-1) to the consensus DNA sequence, a key transcriptional activator of TF expression in response to inflammation, and the expression of Egr-1 mRNA were also inhibited by IL-10. This inhibition was independent of the induction of suppressor of cytokine signaling protein-3 by IL-10. Macrophages that had been transfected with luciferase reporter constructs containing the murine Egr-1 5'-flanking sequence exhibited reduced reporter gene activity in response to LPS stimulation with IL-10 pretreatment. Studies with deletion constructs of the Egr-1 promoter identified the proximal serum response element SRE3 as a potential regulatory site for the IL-10 mediated suppression of Egr-1 expression. Furthermore, activation of the upstream signal-transduction elements, such as mitogen-activated protein kinase kinase (MEK) 1/2, extracellular signal-regulated kinase 1/2, and Elk-1 were also inhibited by IL-10 pretreatment. Taken together, these results demonstrate a pathway for the IL-10 mediated inhibition of TF expression during inflammation and may explain the antiatherosclerotic effects of IL-10.
Circulation Research 09/2005; 97(4):305-13. · 9.49 Impact Factor
