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1.
Willecke F Zeschky K Ortiz Rodriguez A Colberg C Auwärter V Kneisel S Hutter M Lozhkin A Hoppe N Wolf D von zur Mühlen C Moser M Hilgendorf I Bode C Zirlik A 《PloS one》2011,6(4):e19405
Background
Strong evidence supports a protective role of the cannabinoid receptor 2 (CB2) in inflammation and atherosclerosis. However, direct proof of its involvement in lesion formation is lacking. Therefore, the present study aimed to characterize the role of the CB2 receptor in Murine atherogenesis.Methods and Findings
Low density lipoprotein receptor-deficient (LDLR−/−) mice subjected to intraperitoneal injections of the selective CB2 receptor agonist JWH-133 or vehicle three times per week consumed high cholesterol diet (HCD) for 16 weeks. Surprisingly, intimal lesion size did not differ between both groups in sections of the aortic roots and arches, suggesting that CB2 activation does not modulate atherogenesis in vivo. Plaque content of lipids, macrophages, smooth muscle cells, T cells, and collagen were also similar between both groups. Moreover, CB2 −/−/LDLR−/− mice developed lesions of similar size containing more macrophages and lipids but similar amounts of smooth muscle cells and collagen fibers compared with CB2 +/+/LDLR−/− controls. While JWH-133 treatment reduced intraperitoneal macrophage accumulation in thioglycollate-illicited peritonitis, neither genetic deficiency nor pharmacologic activation of the CB2 receptor altered inflammatory cytokine expression in vivo or inflammatory cell adhesion in the flow chamber in vitro.Conclusion
Our study demonstrates that both activation and deletion of the CB2 receptor do not relevantly modulate atherogenesis in mice. Our data do not challenge the multiple reports involving CB2 in other inflammatory processes. However, in the context of atherosclerosis, CB2 does not appear to be a suitable therapeutic target for reduction of the atherosclerotic plaque. 相似文献2.
Fang Yu Fen Du Yuzhen Wang Shengping Huang Ruidong Miao Amy S. Major E. Angela Murphy Mingui Fu Daping Fan 《PloS one》2013,8(11)
Objective
MCPIP1 is a newly identified protein that profoundly impacts immunity and inflammation. We aim to test if MCPIP1 deficiency in hematopoietic cells results in systemic inflammation and accelerates atherogenesis in mice.Approach and Results
After lethally irradiated, LDLR−/− mice were transplanted with bone marrow cells from either wild-type or MCPIP1−/− mice. These chimeric mice were fed a western-type diet for 7 weeks. We found that bone marrow MCPIP1−/− mice displayed a phenotype similar to that of whole body MCPIP1−/− mice, with severe systemic and multi-organ inflammation. However, MCPIP1−/− bone marrow recipients developed >10-fold less atherosclerotic lesions in the proximal aorta than WT bone marrow recipients, and essentially no lesions in en face aorta. The diminishment in atherosclerosis in bone marrow MCPIP1−/− mice may be partially attributed to the slight decrease in their plasma lipids. Flow cytometric analysis of splenocytes showed that bone marrow MCPIP1−/− mice contained reduced numbers of T cells and B cells, but increased numbers of regulatory T cells, Th17 cells, CD11b+/Gr1+ cells and CD11b+/Ly6Clow cells. This overall anti-atherogenic leukocyte profile may also contribute to the reduced atherogenesis. We also examined the cholesterol efflux capability of MCPIP1 deficient macrophages, and found that MCPIP1deficiency increased cholesterol efflux to apoAI and HDL, due to increased protein levels of ABCA1 and ABCG1.Conclusions
Hematopoietic deficiency of MCPIP1 resulted in severe systemic and multi-organ inflammation but paradoxically diminished atherogenesis in mice. The reduced atheroegensis may be explained by the decreased plasma cholesterol levels, the anti-atherogenic leukocyte profile, as well as enhanced cholesterol efflux capability. This study suggests that, while atherosclerosis is a chronic inflammatory disease, the mechanisms underlying atherogenesis-associated inflammation in arterial wall versus the inflammation in solid organs may be substantially different. 相似文献3.
Christina Grothusen Harald Schuett Anja Hillmer Stefan Lumpe Karsten Grote Matthias Ballmaier Andre Bleich Silke Glage Uwe J. F. Tietge Maren Luchtefeld Bernhard Schieffer 《PloS one》2012,7(12)
Background
While the impact of inflammation as the substantial driving force of atherosclerosis has been investigated in detail throughout the years, the influence of negative regulators of pro-atherogenic pathways on plaque development has remained largely unknown. Suppressor of cytokine signaling (SOCS)-1 potently restricts transduction of various inflammatory signals and, thereby modulates T-cell development, macrophage activation and dendritic cell maturation. Its role in atherogenesis, however has not been elucidated so far.Methods and Results
Loss of SOCS-1 in the low-density lipoprotein receptor deficient murine model of atherosclerosis resulted in a complex, systemic and ultimately lethal inflammation with increased generation of Ly-6Chi monocytes and activated macrophages. Even short-term exposure of these mice to high-cholesterol dieting caused enhanced atherosclerotic plaque development with accumulation of M1 macrophages, Ly-6C positive cells and neutrophils.Conclusion
Our data not only imply that SOCS-1 is athero-protective but also emphasize the fundamental, regulatory importance of SOCS-1 in inflammation-prone organisms. 相似文献4.
Erik van Kampen Olivier Beaslas Reeni B. Hildebrand Bart Lammers Theo J. C. Van Berkel Vesa M. Olkkonen Miranda Van Eck 《PloS one》2014,9(10)
Introduction
Oxysterol binding protein Related Proteins (ORPs) mediate intracellular lipid transport and homeostatic regulation. ORP8 downregulates ABCA1 expression in macrophages and cellular cholesterol efflux to apolipoprotein A-I. In line, ORP8 knockout mice display increased amounts of HDL cholesterol in blood. However, the role of macrophage ORP8 in atherosclerotic lesion development is unknown.Methods and Results
LDL receptor knockout (KO) mice were transplanted with bone marrow (BM) from ORP8 KO mice and C57Bl/6 wild type mice. Subsequently, the animals were challenged with a high fat/high cholesterol Western-type diet to induce atherosclerosis. After 9 weeks of Western-Type diet feeding, serum levels of VLDL cholesterol were increased by 50% in ORP8 KO BM recipients compared to the wild-type recipients. However, no differences were observed in HDL cholesterol. Despite the increase in VLDL cholesterol, lesions in mice transplanted with ORP8 KO bone marrow were 20% smaller compared to WT transplanted controls. In addition, ORP8 KO transplanted mice displayed a modest increase in the percentage of macrophages in the lesion as compared to the wild-type transplanted group. ORP8 deficient macrophages displayed decreased production of pro-inflammatory factors IL-6 and TNFα, decreased expression of differentiation markers and showed a reduced capacity to form foam cells in the peritoneal cavity.Conclusions
Deletion of ORP8 in bone marrow-derived cells, including macrophages, reduces lesion progression after 9 weeks of WTD challenge, despite increased amounts of circulating pro-atherogenic VLDL. Reduced macrophage foam cell formation and lower macrophage inflammatory potential are plausible mechanisms contributing to the observed reduction in atherosclerosis. 相似文献5.
Reyhan Nergiz-Unal Judith M. E. M. Cosemans Marion A. H. Feijge Paola E. J. van der Meijden Robert F. Storey J. J. J. van Giezen Mirjam G. A. oude Egbrink Johan W. M. Heemskerk Marijke J. E. Kuijpers 《PloS one》2010,5(4)
Background
In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y12 receptors. However, such models do not predict involvement of P2Y12 in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y12 in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis.Methodology
Plaques in the carotid arteries from Apoe −/− mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y12 blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated.Principal Findings
Acute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y12 blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y12 reduced the thrombi and increased embolization events. These P2Y12 effects were present at shear rates >500 s−1, and they persisted in the presence of coagulation. P2Y12-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding.Conclusions/Significance
Platelet P2Y12 receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y12 function is restricted to high shear flow conditions, and is preserved in the presence of coagulation. 相似文献6.
7.
Background
Apolipoprotein E (ApoE), a cholesterol carrier associated with atherosclerosis, is a major risk factor for Alzheimer''s disease (AD). The low-density lipoprotein receptor (LDLR) regulates ApoE levels in the periphery and in the central nervous system. LDLR has been identified on astrocytes and a number of studies show that it modulates amyloid deposition in AD transgenic mice. However these findings are controversial on whether LDLR deletion is beneficial or detrimental on the AD-like phenotype of the transgenic mice.Methodology/Principal Findings
To investigate the role of LDLR in the development of the amyloid related phenotype we used an APP/PS1 transgenic mouse (5XFAD) that develops an AD-like pathology with amyloid plaques, astrocytosis and microgliosis. We found that 4 months old 5XFAD transgenic mice on the LDLR deficient background (LDLR-/-) have increased amyloid plaque deposition. This increase is associated with a significant decrease in astrocytosis and microgliosis in the 5XFAD/LDLR-/- mice. To further elucidate the role of LDLR in relation with ApoE we have generated 5XFAD transgenic mice on the ApoE deficient (ApoE-/-) or the ApoE/LDLR double deficient background (ApoE-/-/LDLR -/-). We have found that ApoE deletion in the 4 months old 5XFAD/ApoE-/- mice decreases amyloid plaque formation as expected, but has no effect on astrocytosis or microgliosis. By comparison 5XFAD/ApoE-/-LDLR -/- double deficient mice of the same age have increased amyloid deposition with decreased astrocytosis and microgliosis.Conclusions
Our analysis shows that LDL deficiency regulates astrocytosis and microgliosis in an AD mouse model. This effect is independent of ApoE, as both 5XFAD/LDLR -/- and 5XFAD/ApoE-/- LDLR -/- mice show reduction in inflammatory response and increase in amyloid deposition compared to control mice. These results demonstrate that LDLR regulates glial response in this mouse model independently of ApoE and modifies amyloid deposition. 相似文献8.
Holm S Ueland T Dahl TB Michelsen AE Skjelland M Russell D Nymo SH Krohg-Sørensen K Clausen OP Atar D Januzzi JL Aukrust P Jensen JK Halvorsen B 《PloS one》2011,6(12):e28785
Background and Purpose
Fatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke.Methods
We examined plasma FABP4 levels in asymptomatic (n = 28) and symptomatic (n = 31) patients with carotid atherosclerosis, as well as in 202 subjects with acute ischemic stroke. In a subgroup of patients we also analysed the expression of FABP4 within the atherosclerotic lesion. In addition, we investigated the ability of different stimuli with relevance to atherosclerosis to regulate FABP4 expression in monocytes/macrophages.Results
FABP4 levels were higher in patients with carotid atherosclerosis, both systemically and within the atherosclerotic lesion, with particular high mRNA levels in carotid plaques from patients with the most recent symptoms. Immunostaining of carotid plaques localized FABP4 to macrophages, while activated platelets and oxidized LDL were potent stimuli for FABP4 expression in monocytes/macrophages in vitro. When measured at the time of acute ischemic stroke, high plasma levels of FABP4 were significantly associated with total and cardiovascular mortality during follow-up, although we did not find that addition of FABP4 to the fully adjusted multivariate model had an effect on the prognostic discrimination for all-cause mortality as assessed by c-statistics.Conclusions
FABP4 is linked to atherogenesis, plaque instability and adverse outcome in patients with carotid atherosclerosis and acute ischemic stroke. 相似文献9.
Background
We recently demonstrated that tyrosine sulfation is an important contributor to monocyte recruitment and retention in a mouse model of atherosclerosis. P-selectin glycoprotein ligand-1 (Psgl-1) is tyrosine-sulfated in mouse monocyte/macrophages and its interaction with P-selectin is important in monocyte recruitment in atherosclerosis. However, whether tyrosine sulfation is required for the P-selectin binding function of mouse Psgl-1 is unknown. Here we test the function of native Psgl-1 expressed in leukocytes lacking endogenous tyrosylprotein sulfotransferase (TPST) activity.Methodology/Principal Findings
Psgl-1 function was assessed by examining P-selectin dependent leukocyte rolling in post-capillary venules of C57BL6 mice transplanted with hematopoietic progenitors from wild type (WT→B6) or Tpst1;Tpst2 double knockout mice (Tpst DKO→B6) which lack TPST activity. We observed that rolling flux fractions were lower and leukocyte rolling velocities were higher in Tpst DKO→B6 venules compared to WT→B6 venules. Similar results were observed on immobilized P-selectin in vitro. Finally, Tpst DKO leukocytes bound less P-selectin than wild type leukocytes despite equivalent surface expression of Psgl-1.Conclusions/Significance
These findings provide direct and convincing evidence that tyrosine sulfation is required for optimal function of mouse Psgl-1 in vivo and suggests that tyrosine sulfation of Psgl-1 contributes to the development of atherosclerosis. 相似文献10.
Peter Stachon Anna Missiou Carina Walter Nerea Varo Christian Colberg Dennis Wolf Maike Buchner Constantin von zur Mühlen Katja Zirlik Christoph Bode Andreas Zirlik 《PloS one》2010,5(7)
Background
Tumor necrosis factor receptor-associated factors (TRAFs) are important signaling molecules for a variety of pro-atherogenic cytokines including CD40L, TNF α, and IL1β. Several lines of evidence identified TRAF6 as a pro-inflammatory signaling molecule in vitro and we previously demonstrated overexpression of TRAF6 in human and Murine atherosclerotic plaques. This study investigated the role of TRAF6-deficiency in mice developing atherosclerosis, a chronic inflammatory disease.Methodology/Principal Findings
Lethally irradiated low density lipoprotein receptor-deficient mice (TRAF6+/+/LDLR−/−) were reconstituted with TRAF6-deficient fetal liver cells (FLC) and consumed high cholesterol diet for 18 weeks to assess the relevance of TRAF6 in hematopoietic cells for atherogenesis. Additionally, TRAF6+/−/LDLR−/− mice received TRAF6-deficient FLC to gain insight into the role of TRAF6 deficiency in resident cells. Surprisingly, atherosclerotic lesion size did not differ between the three groups in both aortic roots and abdominal aortas. Similarly, no significant differences in plaque composition could be observed as assessed by immunohistochemistry for macrophages, lipids, smooth muscle cells, T-cells, and collagen. In accord, in a small clinical study TRAF6/GAPDH total blood RNA ratios did not differ between groups of patients with stable coronary heart disease (0.034±0.0021, N = 178), acute coronary heart disease (0.029±0.0027, N = 70), and those without coronary heart disease (0.032±0.0016, N = 77) as assessed by angiography.Conclusion
Our study demonstrates that TRAF6 is not required for atherogenesis in mice and does not associate with clinical disease in humans. These data suggest that pro- and anti-inflammatory features of TRAF6 signaling outweigh each other in the context of atherosclerosis. 相似文献11.
Binggang Xiang Guoying Zhang Hongmei Ren Manjula Sunkara Andrew J. Morris T. Kent Gartner Susan S. Smyth Zhenyu Li 《PloS one》2012,7(12)
Background
ADP is an important physiological agonist that induces integrin activation and platelet aggregation through its receptors P2Y1 (Gαq-coupled) and P2Y12 (Gαi-coupled). P2Y12 plays a critical role in platelet activation and thrombosis. Adenosine-based P2Y12 antagonists, 2-methylthioadenosine 5′-monophosphate triethylammonium salt hydrate (2MeSAMP) and Cangrelor (AR-C69931MX) have been widely used to demonstrate the role of P2Y12 in platelet function. Cangrelor is being evaluated in clinical trials of thrombotic diseases. However, a recent study reported that both 2MeSAMP and Cangrelor raise intra-platelet cAMP levels and inhibit platelet aggregation through a P2Y12-independent mechanism.Methodology/Principal Findings
The present work, using P2Y12 deficient mice, sought to clarify previous conflicting reports and to elucidate the mechanisms by which 2MeSAMP and Cangrelor inhibit platelet activation and thrombosis. 2MeSAMP and Cangrelor inhibited aggregation and ATP release of wild-type but not P2Y12 deficient platelets. 2MeSAMP and Cangrelor neither raised intracellular cAMP concentrations nor induced phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in washed human or mouse platelets. Furthermore, unlike the activators (PGI2 and forskolin) of the cAMP pathway, 2MeSAMP and Cangrelor failed to inhibit Ca2+ mobilization, Akt phosphorylation, and Rap1b activation in P2Y12 deficient platelets. Importantly, while injection of Cangrelor inhibited thrombus formation in a FeCl3-induced thrombosis model in wild-type mice, it failed to affect thrombus formation in P2Y12 deficient mice.Conclusions
These data together demonstrate that 2MeSAMP and Cangrelor inhibit platelet function through the P2Y12-dependent mechanism both in vitro and in vivo. 相似文献12.
Katelijne O De Swert Ken R Bracke Tine Demoor Guy G Brusselle Guy F Joos 《Respiratory research》2009,10(1):37
Background
The tachykinins, substance P and neurokinin A, present in sensory nerves and inflammatory cells such as macrophages and dendritic cells, are considered as pro-inflammatory agents. Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and increased tachykinin levels are recovered from the airways of COPD patients. The aim of our study was to clarify the involvement of the tachykinin NK1 receptor, the preferential receptor for substance P, in cigarette smoke (CS)-induced pulmonary inflammation and emphysema in a mouse model of COPD.Methods
Tachykinin NK1 receptor knockout (NK1-R-/-) mice and their wild type controls (all in a mixed 129/sv-C57BL/6 background) were subjected to sub acute (4 weeks) or chronic (24 weeks) exposure to air or CS. 24 hours after the last exposure, pulmonary inflammation and development of emphysema were evaluated.Results
Sub acute and chronic exposure to CS resulted in a substantial accumulation of inflammatory cells in the airways of both WT and NK1-R-/- mice. However, the CS-induced increase in macrophages and dendritic cells was significantly impaired in NK1-R-/- mice, compared to WT controls, and correlated with an attenuated release of MIP-3α/CCL20 and TGF-β1. Chronic exposure to CS resulted in development of pulmonary emphysema in WT mice. NK1-R-/- mice showed already enlarged airspaces upon air-exposure. Upon CS-exposure, the NK1-R-/- mice did not develop additional destruction of the lung parenchyma. Moreover, an impaired production of MMP-12 by alveolar macrophages upon CS-exposure was observed in these KO mice. In a pharmacological validation experiment using the NK1 receptor antagonist RP 67580, we confirmed the protective effect of absence of the NK1 receptor on CS-induced pulmonary inflammation.Conclusion
These data suggest that the tachykinin NK1 receptor is involved in the accumulation of macrophages and dendritic cells in the airways upon CS-exposure and in the development of smoking-induced emphysema. As both inflammation of the airways and parenchymal destruction are important characteristics of COPD, these findings may have implications in the future treatment of this devastating disease. 相似文献13.
Maekawa T Takahashi N Tabeta K Aoki Y Miyashita H Miyauchi S Miyazawa H Nakajima T Yamazaki K 《PloS one》2011,6(5):e20240
Background
Recent studies have suggested that periodontal disease increases the risk of atherothrombotic disease. Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in the arteries. Although several studies have suggested that certain periodontopathic bacteria accelerate atherogenesis in apolipoprotein E-deficient mice, the mechanistic link between cholesterol accumulation and periodontal infection-induced inflammation is largely unknown.Methodology/Principal Findings
We orally infected C57BL/6 and C57BL/6.KOR-Apoeshl (B6.Apoeshl) mice with Porphyromonas gingivalis, which is a representative periodontopathic bacterium, and evaluated atherogenesis, gene expression in the aorta and liver and systemic inflammatory and lipid profiles in the blood. Furthermore, the effect of lipopolysaccharide (LPS) from P. gingivalis on cholesterol transport and the related gene expression was examined in peritoneal macrophages. Alveolar bone resorption and elevation of systemic inflammatory responses were induced in both strains. Despite early changes in the expression of key genes involved in cholesterol turnover, such as liver X receptor and ATP-binding cassette A1, serum lipid profiles did not change with short-term infection. Long-term infection was associated with a reduction in serum high-density lipoprotein (HDL) cholesterol but not with the development of atherosclerotic lesions in wild-type mice. In B6.Apoeshl mice, long-term infection resulted in the elevation of very low-density lipoprotein (VLDL), LDL and total cholesterols in addition to the reduction of HDL cholesterol. This shift in the lipid profile was concomitant with a significant increase in atherosclerotic lesions. Stimulation with P. gingivalis LPS induced the change of cholesterol transport via targeting the expression of LDL receptor-related genes and resulted in the disturbance of regulatory mechanisms of the cholesterol level in macrophages.Conclusions/Significance
Periodontal infection itself does not cause atherosclerosis, but it accelerates it by inducing systemic inflammation and deteriorating lipid metabolism, particularly when underlying hyperlidemia or susceptibility to hyperlipidemia exists, and it may contribute to the development of coronary heart disease. 相似文献14.
Julian Jehle Friedrich Felix Hoyer Benedikt Sch?ne Philipp Pfeifer Katharina Schild Imke Jenniches Laura Bindila Beat Lutz Dieter Lütjohann Andreas Zimmer Georg Nickenig 《PloS one》2016,11(1)
Background
The endocannabinoid 2-arachidonoylglycerol (2-AG) is a known modulator of inflammation. Despite its high concentration in vascular tissue, the role of 2-AG in atherogenesis has not yet been examined.Methods
ApoE-deficient mice were sublethally irradiated and reconstituted with bone marrow from mice with a myeloid-specific knockout of the 2-AG synthesising enzyme diacylglycerol lipase α (Dagla) or control bone marrow with an intact 2-AG biosynthesis. After a cholesterol-rich diet for 8 weeks, plaque size and plaque morphology were examined in chimeric mice. Circulating inflammatory cells were assessed by flow cytometry. Aortic tissue and plasma levels of endocannabinoids were measured using liquid chromatography-multiple reaction monitoring.Results
Mice with Dagla-deficient bone marrow and circulating myeloid cells showed a significantly reduced plaque burden compared to controls. The reduction in plaque size was accompanied by a significantly diminished accumulation of both neutrophil granulocytes and macrophages in atherosclerotic lesions of Dagla-deficient mice. Moreover, CB2 expression and the amount of oxidised LDL within atherosclerotic lesions was significantly reduced. FACS analyses revealed that levels of circulating inflammatory cells were unaltered in Dagla-deficient mice.Conclusions
Myeloid synthesis of the endocannabinoid 2-AG appears to promote vascular inflammation and atherogenesis. Thus, myeloid-specific disruption of 2-AG synthesis may represent a potential novel therapeutic strategy against atherosclerosis. 相似文献15.
Wouters K Cudejko C Gijbels MJ Fuentes L Bantubungi K Vanhoutte J Dièvart R Paquet C Bouchaert E Hannou SA Gizard F Tailleux A de Winther MP Staels B Paumelle R 《PloS one》2012,7(3):e32440
Objective
A genomic region near the CDKN2A locus, encoding p16INK4a, has been associated to type 2 diabetes and atherosclerotic vascular disease, conditions in which inflammation plays an important role. Recently, we found that deficiency of p16INK4a results in decreased inflammatory signaling in murine macrophages and that p16INK4a influences the phenotype of human adipose tissue macrophages. Therefore, we investigated the influence of immune cell p16INK4a on glucose tolerance and atherosclerosis in mice.Methods and Results
Bone marrow p16INK4a-deficiency in C57Bl6 mice did not influence high fat diet-induced obesity nor plasma glucose and lipid levels. Glucose tolerance tests showed no alterations in high fat diet-induced glucose intolerance. While bone marrow p16INK4a-deficiency did not affect the gene expression profile of adipose tissue, hepatic expression of the alternative markers Chi3l3, Mgl2 and IL10 was increased and the induction of pro-inflammatory Nos2 was restrained on the high fat diet. Bone marrow p16INK4a-deficiency in low density lipoprotein receptor-deficient mice did not affect western diet-induced atherosclerotic plaque size or morphology. In line, plasma lipid levels remained unaffected and p16INK4a-deficient macrophages displayed equal cholesterol uptake and efflux compared to wild type macrophages.Conclusion
Bone marrow p16INK4a-deficiency does not affect plasma lipids, obesity, glucose tolerance or atherosclerosis in mice. 相似文献16.
BL Vaisman KL Andrews SM Khong KC Wood XL Moore Y Fu DM Kepka-Lenhart SM Morris AT Remaley JP Chin-Dusting 《PloS one》2012,7(7):e39487
Background
Cardiovascular disorders associated with endothelial dysfunction, such as atherosclerosis, have decreased nitric oxide (NO) bioavailability. Arginase in the vasculature can compete with eNOS for L-arginine and has been implicated in atherosclerosis. The aim of this study was to evaluate the effect of endothelial-specific elevation of arginase II expression on endothelial function and the development of atherosclerosis.Methodology/Principal Findings
Transgenic mice on a C57BL/6 background with endothelial-specific overexpression of human arginase II (hArgII) gene under the control of the Tie2 promoter were produced. The hArgII mice had elevated tissue arginase activity except in liver and in resident peritoneal macrophages, confirming endothelial specificity of the transgene. Using small-vessel myography, aorta from these mice exhibited endothelial dysfunction when compared to their non-transgenic littermate controls. The blood pressure of the hArgII mice was 17% higher than their littermate controls and, when crossed with apoE −/− mice, hArgII mice had increased aortic atherosclerotic lesions.Conclusion
We conclude that overexpression of arginase II in the endothelium is detrimental to the cardiovascular system. 相似文献17.
Lars Knudsen Elena N. Atochina-Vasserman Chang-Jiang Guo Pamela A. Scott Beat Haenni Michael F. Beers Matthias Ochs Andrew J. Gow 《PloS one》2014,9(1)
Rationale
Surfactant protein D (SP-D) has important immuno-modulatory properties. The absence of SP-D results in an inducible NO synthase (iNOS, coded by NOS2 gene) related chronic inflammation, development of emphysema-like pathophysiology and alterations of surfactant homeostasis.Objective
In order to test the hypothesis that SP-D deficiency related abnormalities in pulmonary structure and function are a consequence of iNOS induced inflammation, we generated SP-D and iNOS double knockout mice (DiNOS).Methods
Structural data obtained by design-based stereology to quantify the emphysema-like phenotype and disturbances of the intracellular surfactant were correlated to invasive pulmonary function tests and inflammatory markers including activation markers of alveolar macrophages and compared to SP-D (Sftpd−/−) and iNOS single knockout mice (NOS2−/−) as well as wild type (WT) littermates.Measurements and Results
DiNOS mice had reduced inflammatory cells in BAL and BAL-derived alveolar macrophages showed an increased expression of markers of an alternative activation as well as reduced inflammation. As evidenced by increased alveolar numbers and surface area, emphysematous changes were attenuated in DiNOS while disturbances of the surfactant system remained virtually unchanged. Sftpd−/− demonstrated alterations of intrinsic mechanical properties of lung parenchyma as shown by reduced stiffness and resistance at its static limits, which could be corrected by additional ablation of NOS2 gene in DiNOS.Conclusion
iNOS related inflammation in the absence of SP-D is involved in the emphysematous remodeling leading to a loss of alveoli and associated alterations of elastic properties of lung parenchyma while disturbances of surfactant homeostasis are mediated by different mechanisms. 相似文献18.
van Haperen R Samyn H Moerland M van Gent T Peeters M Grosveld F van Tol A de Crom R 《PloS one》2008,3(5):e2255
Background
Phospholipid transfer protein (PLTP) is expressed by various cell types. In plasma, it is associated with high density lipoproteins (HDL). Elevated levels of PLTP in transgenic mice result in decreased HDL and increased atherosclerosis. PLTP is present in human atherosclerotic lesions, where it seems to be macrophage derived. The aim of the present study is to evaluate the atherogenic potential of macrophage derived PLTP.Methods and Findings
Here we show that macrophages from human PLTP transgenic mice secrete active PLTP. Subsequently, we performed bone marrow transplantations using either wild type mice (PLTPwt/wt), hemizygous PLTP transgenic mice (huPLTPtg/wt) or homozygous PLTP transgenic mice (huPLTPtg/tg) as donors and low density lipoprotein receptor deficient mice (LDLR−/−) as acceptors, in order to establish the role of PLTP expressed by bone marrow derived cells in diet-induced atherogenesis. Atherosclerosis was increased in the huPLTPtg/wt→LDLR−/− mice (2.3-fold) and even further in the huPLTPtg/tg→LDLR−/− mice (4.5-fold) compared with the control PLTPwt/wt→LDLR−/− mice (both P<0.001). Plasma PLTP activity levels and non-HDL cholesterol were increased and HDL cholesterol decreased compared with controls (all P<0.01). PLTP was present in atherosclerotic plaques in the mice as demonstrated by immunohistochemistry and appears to co-localize with macrophages. Isolated macrophages from PLTP transgenic mice do not show differences in cholesterol efflux or in cytokine production. Lipopolysaccharide activation of macrophages results in increased production of PLTP. This effect was strongly amplified in PLTP transgenic macrophages.Conclusions
We conclude that PLTP expression by bone marrow derived cells results in atherogenic effects on plasma lipids, increased PLTP activity, high local PLTP protein levels in the atherosclerotic lesions and increased atherosclerotic lesion size. 相似文献19.
Emilie Lyne Saussereau Delphine Roussel Siradiou Diallo Laurent Debarbieux Aleksander Edelman Isabelle Sermet-Gaudelus 《PloS one》2013,8(3)
Background
Treatments designed to correct cystic fibrosis transmembrane conductance regulator (CFTR) defects must first be evaluated in preclinical experiments in the mouse model of cystic fibrosis (CF). Mice nasal mucosa mimics the bioelectric defect seen in humans. The use of nasal potential difference (VTE) to assess ionic transport is a powerful test evaluating the restoration of CFTR function. Nasal VTE in CF mice must be well characterized for correct interpretation.Methods
We performed VTE measurements in large-scale studies of two mouse models of CF—B6;129 cftr knockout and FVB F508del-CFTR—and their respective wild-type (WT) littermates. We assessed the repeatability of the test for cftr knockout mice and defined cutoff points distinguishing between WT and F508del-CFTR mice.Results
We determined the typical VTE values for CF and WT mice and demonstrated the existence of residual CFTR activity in F508del-CFTR mice. We characterized intra-animal variability in B6;129 mice and defined the cutoff points for F508del-CFTR chloride secretion rescue. Hyperpolarization of more than -2.15 mV after perfusion with a low-concentration Cl- solution was considered to indicate a normal response.Conclusions
These data will make it possible to interpret changes in nasal VTE in mouse models of CF, in future preclinical studies. 相似文献20.
Anatoly N Mikerov Xiaozhuang Gan Todd M Umstead Laura Miller Vernon M Chinchilli David S Phelps Joanna Floros 《Respiratory research》2008,9(1):24