Abstract 156: Macrophage Low-Density Receptor--Related Protein 1 Deficiency Facilitates Atherosclerosis Regression in Hyperlipidemic Mice

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Lin Zhu ◽  
Patricia G Yancey ◽  
Lei Ding ◽  
John L Blakemore ◽  
Youmin Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Chow Diet ◽  
Low Density ◽  
Related Protein ◽  
Wild Type ◽  
Lesion Area ◽  
Cholesterol Levels ◽  
Inflammatory Macrophages

Atherosclerosis regression is characterized by egress of macrophages out of the artery wall. We have previously shown that macrophages lacking low-density receptor related protein 1 (MFLRP1-/-) are pro-inflammatory and lead to increased lesion formation in apoE-/- mice. To study the role of macrophage inflammation during atherosclerosis regression, bone marrow from four different types of mice (wild-type, MFLRP1-/-, apoE-/- and apoE-/-/ MFLRP1-/-) was transplanted into apoE-/- recipient mice who had been fed a Western-type diet for 12 weeks. ApoE-/- recipient mice transplanted with apoE-/- bone marrow were sacrificed 2 weeks post-BMT for determination of baseline aortic atherosclerosis. After 8 weeks on chow diet, cholesterol levels were normalized in mice reconstituted with wild-type (WT) and MFLRP1-/- bone marrow (157± 36 mg/dl and 136 ± 33 mg/dl, respectively), and significantly lowered in mice with apoE-/- (302±33 mg/dl) or apoE-/-/ MFLRP1-/- (294±52 mg/dl) macrophages compared to baseline (387±34 mg/dl). Total atherosclerotic lesion area in the aortic root decreased by 15% in mice receiving WT macrophages, and decreased by an additional 10% in mice transplanted with LRP1 deficient macrophages (p<0.05 compared to WT). Similarly, mice reconstituted with apoE-/-/ MFLRP1-/- bone marrow had 15% (p < 0.01) smaller lesion size than mice receiving apoE-/- marrow. The lesion area positive for CD68 was significantly smaller in MFLRP1-/- mice compared to WT mice, and in apoE-/-/ MFLRP1-/- mice compared to apoE-/- mice. The ratio of necrotic to total lesion area was significantly lowered by WT and LRP1-/- macrophages, and was also reduced in recipients of apoE-/-/MFLRP1-/- compared to apoE-/- bone marrow. Here we demonstrate that absence of LRP1 in macrophages, which is known to cause pro-inflammatory changes, promotes atherosclerosis regression. Our study supports the novel idea that pro-inflammatory macrophages efficiently egress from the plaque in a regressive environment caused by switching from a high-fat to a chow diet. This observation sets the stage for a change in paradigm on how to target inflammation for prevention of atherosclerotic cardiovascular events.

Abstract 463: TLT-1 Deficiency Affects Hypercholesterolemia and Progression of the Atherosclerotic Plaque in Apoe Null Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Marieli Gonzalez ◽  
Fiorella Reyes ◽  
Deborah Marrero ◽  
A V Washington
Keyword(s):  
Platelet Activation ◽  
Inflammatory Responses ◽  
Plaque Rupture ◽  
Atherosclerotic Lesion ◽  
Soluble Form ◽  
Chow Diet ◽  
Fatty Streak ◽  
Wild Type ◽  
Platelet Surface ◽  
Cholesterol Levels

Platelet activation at sites of inflammation triggers the secretion of molecules that induce the transition of atherosclerosis from fatty streak to an acute disease, featuring an increased vulnerability of the atherosclerotic lesion that results in plaque rupture and thrombosis. TLT-1 (Triggering Receptor Expressed in Myeloid cells (TREM)-like transcript-1) is a molecule exclusively found in the α-granules of megakarocytes and platelets and has a demonstrated effect in inflammatory responses. Upon platelet activation, TLT-1 is moved to the platelet surface, while its soluble form, s-TLT-1, is secreted and detected in serum. Studies using the C57Bl/6 treml1 - /- mouse demonstrated a predisposition to hemorrhage after an acute inflammatory challenge suggesting that TLT-1 may be a key regulatory molecule in the interface between hemostatic and inflammatory mechanisms. Because we have found that sTLT-1 levels are significantly elevated in apoE mice when compared to wild type, we hypothesized that TLT-1 may be playing an important role in the progression of atherosclerosis. To address this possibility, we generated apoE - /- / treml1 - /- double knockout mice [DN]. Assessment of lesions after 4 weeks high-fat diet (HFD) demonstrated that at early stages, TLT-1 deficiency accelerates fatty streak formation. After 20 weeks on HFD, lesions in both apoE - /- and [DN] mice progressed to an advance fibrous plaque stage. Although their lesion sizes were not substantially different, lesion compositions were. The mechanistic basis of these differences appears to be that the [DN] mice have significantly higher cholesterol levels when compared to apoE - /- mice. The increased cholesterol levels extend to the treml1 -/- mouse when compared to wild type mice at 4 weeks on HFD, this difference, however, gradually subsides as wild type mice cholesterol levels increase over 20 weeks. Interestingly, cholesterol levels in 50 week old mice on chow diet revealed minimal differences between test and control mice suggesting the higher cholesterol levels are related to increased dietary intake. Our work defines a surprising role for TLT-1 in the regulation of serum cholesterol levels during atherogenesis.

Abstract 17163: Nox4 Deletion Attenuates Age-Associated Vascular Inflammation and Atherosclerosis Burden in Hyperlipidemic Mice by Modulating Macrophage Phenotype

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Aleksandr E Vendrov ◽  
Andrey Lozhkin ◽  
Nageswara R Madamanchi ◽  
Marschall S Runge
Keyword(s):  
Vascular Inflammation ◽  
Atherosclerotic Lesion ◽  
Inflammasome Activation ◽  
Macrophage Phenotype ◽  
Wild Type ◽  
Lesion Area ◽  
Atherosclerotic Lesions ◽  
M1 Phenotype ◽  
Inflammatory Macrophages ◽  
Lps Treatment

Introduction: Increased vascular reactive oxygen species (ROS) levels and chronic inflammation are hallmarks of vascular aging. We previously reported that expression of NOX4 NADPH oxidase increases with age in mouse and human arteries and correlates with inflammatory cytokine secretion and atherosclerotic lesion progression. Hypothesis: To determine whether NOX4 promotes atherosclerosis in aging, we assessed vascular inflammation and atherosclerosis burden in Nox4 -/- / Apoe -/- and Apoe -/- mice. Results: Aortic atherosclerotic lesion area was not different between 5-month old (young) Nox4 -/- / Apoe -/- and Apoe -/- mice fed a Western diet for 3 months. Lesion area increased significantly in 16-month old (aged) compared with young mice but was 51% lower in Nox 4 -/- / Apoe -/- versus Apoe -/- mice (n=12, P <0.0001). Immunofluorescence analysis of aorta transverse sections showed 30% lower ROS levels and significantly reduced expression of inflammatory cytokines - CCL2 and IL6 - in atherosclerotic lesions of aged Nox4 -/- / Apoe -/- versus Apoe -/- mice. Flow cytometry analysis of atherosclerotic aortas showed significantly higher number of CD11b + macrophages in the lesions of aged Apoe -/- versus Nox4 -/- /Apoe -/- mice. However, the number of M1 pro-inflammatory macrophages (CD38 + ) was not different, whereas percentage of M2 macrophages (Egr2 + ) was significantly higher in aged Nox4 -/- Apoe -/- versus Apoe -/- mice (46% vs. 33%, respectively). In addition, Nox4 deletion increased the ratio of M2/M1 macrophages in the atherosclerotic aortas from aged Apoe -/- mice (0.56 and 0.43 in Nox 4 -/- / Apoe -/- and Apoe -/- , respectively). Macrophages isolated from Nox4 -/- mice showed lower number of M1 cells after IFNγ+LPS treatment and higher number of M2 cells after IL4 treatment versus macrophages from the wild-type. Furthermore, wild-type macrophages showed significantly higher secreted IL1β levels after IFNγ+LPS treatment versus macrophages from Nox4 -/- mice. Conclusions: These data suggest that increased vascular NOX4 levels in aged Apoe -/- mice promote a proinflammatory environment, enhancing plaque macrophage accumulation and skewing polarization to M1 phenotype resulting in inflammasome activation and atherosclerotic lesion expansion.

Maternal high-fat feeding in pregnancy programs atherosclerotic lesion size in the ApoE*3 Leiden mouse

2016 ◽  
Vol 7 (3) ◽  
pp. 290-297 ◽  
Author(s):  
E. J. Tarling ◽  
K. J. P. Ryan ◽  
R. Austin ◽  
S. J. Kugler ◽  
A. M. Salter ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Maternal Diet ◽  
Atherosclerotic Lesion ◽  
Plasma Lipid ◽  
Lesion Size ◽  
Atherogenic Diet ◽  
Chow Diet ◽  
Wild Type ◽  
High Fat ◽  
Cell Proliferation And Differentiation

Periods of rapid growth seen during the early stages of fetal development, including cell proliferation and differentiation, are greatly influenced by the maternal environment. We demonstrate here that over-nutrition, specifically exposure to a high-fat dietin utero, programed the extent of atherosclerosis in the offspring of ApoE*3 Leiden transgenic mice. Pregnant ApoE*3 Leiden mice were fed either a control chow diet (2.8% fat,n=12) or a high-fat, moderate-cholesterol diet (MHF, 19.4% fat,n=12). Dams were fed the chow diet during the suckling period. At 28 days postnatal age wild type and ApoE*3 Leiden offspring from chow or MHF-fed mothers were fed either a control chow diet (n=37) or a diet rich in cocoa butter (15%) and cholesterol (0.25%), for 14 weeks to induce atherosclerosis (n=36). Offspring from MHF-fed mothers had 1.9-fold larger atherosclerotic lesions (P<0.001). There was no direct effect of prenatal diet on plasma triglycerides or cholesterol; however, transgenic ApoE*3 Leiden offspring displayed raised cholesterol when on an atherogenic diet compared with wild-type controls (P=0.031). Lesion size was correlated with plasma lipid parameters after adjustment for genotype, maternal diet and postnatal diet (R2=0.563,P<0.001). ApoE*3 Leiden mothers fed a MHF diet developed hypercholesterolemia (plasma cholesterol two-fold higher than in chow-fed mothers,P=0.011). The data strongly suggest that maternal hypercholesterolemia programs later susceptibility to atherosclerosis. This is consistent with previous observations in humans and animal models.

scholarly journals Reduced Atherosclerotic Lesion Size inP-Selectin Deficient ApolipoproteinE-Knockout Mice Fed a Chow but Not a Fat Diet

2006 ◽  
Vol 2006 ◽  
pp. 1-8 ◽  
Author(s):  
Marie-Claude Bourdillon ◽  
Jacques Randon ◽  
Lydie Barek ◽  
Kazem Zibara ◽  
Chantal Covacho ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Vascular Lesions ◽  
Chow Diet ◽  
Double Knockout ◽  
Beneficial Effects ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels ◽  
Human Arteries ◽  
Lower Ratio

Endothelial cells lining atherosclerotic, but not healthy sites, on human arteries expressP-selectin. We investigated the role ofP-selectin on the development of vascular lesions in an ApoE−/−male mice. Double-knockout (ApoE−/−,P-selectin-/-; DKO) were compared to single-knockout (ApoE−/−; SKO) mice. They were fed a chow or fat diet for 3, 6, 15, and 20 weeks, without any differences in cholesterol levels. DKO mice fed a chow diet exhibited a ratio of lesion area over media lower than SKO mice, for 3 (P<.03) , 6 (P<.001), and 15 (P<.02) weeks. DKO mice fed a fat diet showed a lower ratio only at 3 weeks.P-selectin deficiency in ApoE−/−mice has a protective effect in atherosclerotic lesions development. Reduction of lesion size depends on diet type and duration. A fat diet could neutralize the beneficial effects ofP-selectin deficiency, inducing atherosclerotic lesions via probably other adhesion molecules.

Abstract 104: Apolipoprotein D: Implications for Multiple Roles in Lipid Metabolism

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Ujala Srivastava ◽  
Ehab M Abo-Ali ◽  
Susanna Nguy ◽  
Jean Lebegue ◽  
Kamilah Ali
Keyword(s):  
Lipid Metabolism ◽  
Plasma Cholesterol ◽  
Atherosclerotic Lesion ◽  
Minor Component ◽  
Chow Diet ◽  
Lcat Activity ◽  
Wild Type ◽  
Cholesterol Acyl Transferase ◽  
Cholesterol Levels ◽  
Significant Difference

Introduction- ApoD is a ubiquitously expressed protein that binds small hydrophobic ligands and is a minor component of lipoproteins. Polymorphisms of the human ApoD gene are associated with lipid abnormalities, specifically the reduction of HDL and ApoA1 levels. In fact, hepatic overexpression of ApoD has been shown to regulate the amount of plasma triglycerides. ApoD is also upregulated in human and mouse models of atherosclerosis, and is localized in cell types involved in atherosclerotic lesion formation. These data suggest that ApoD plays a role in lipid metabolism by modulating cellular processes in vascular cells during atherogenesis. In this study, our objective is to identify the role(s) of ApoD in lipid metabolism and to elucidate the mechanisms involved in this process. Methods and Results- To accomplish our objective, we used a two-pronged approach. We first studied the effect of ApoD on lipid metabolism on a chow diet. There was no significant difference between the levels of plasma cholesterol in ApoD -/- and wild-type mice on a chow diet; however, hepatic cholesterol levels had more than doubled. A 96-gene PCR array was used to assess differential expression of genes involved in fatty liver biogenesis. There was at least a 2-fold difference in expression in about 10 genes involved in insulin/glucose signaling, lipogenesis, and inflammation in the ApoD -/- mice. We then studied the effect of a Western diet in the ApoD -/- mice, which showed a significant reduction in plasma LDL-cholesterol and HDL-cholesterol when compared to wild-type mice. Analysis of the HDL fractions after subjecting plasma to a Fast Protein Liquid Chromatography column revealed increased levels of ApoA1 and Lecithin Cholesterol Acyl Transferase (LCAT) activity in ApoD -/- mice. Conclusion- A decrease in plasma cholesterol and an increase in ApoA1 and LCAT activity suggest that ApoD may play a role in the catabolism of HDL particles, resulting in lower plasma cholesterol levels in ApoD -/- mice. Our current data implies that ApoD plays a multifunctional role in lipid metabolism and the mechanism by which this occurs must be further examined.

scholarly journals Androgen Receptor-Dependent and Independent Atheroprotection by Testosterone in Male Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5428-5437 ◽  
Author(s):  
Johan Bourghardt ◽  
Anna S. K. Wilhelmson ◽  
Camilla Alexanderson ◽  
Karel De Gendt ◽  
Guido Verhoeven ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Apolipoprotein E ◽  
High Fat Diet ◽  
Atherosclerotic Lesion ◽  
Male Mice ◽  
Wild Type ◽  
High Fat ◽  
Lesion Area ◽  
Major Pathway

The atheroprotective effect of testosterone is thought to require aromatization of testosterone to estradiol, but no study has adequately addressed the role of the androgen receptor (AR), the major pathway for the physiological effects of testosterone. We used AR knockout (ARKO) mice on apolipoprotein E-deficient background to study the role of the AR in testosterone atheroprotection in male mice. Because ARKO mice are testosterone deficient, we sham operated or orchiectomized (Orx) the mice before puberty, and Orx mice were supplemented with placebo or a physiological testosterone dose. From 8 to 16 wk of age, the mice consumed a high-fat diet. In the aortic root, ARKO mice showed increased atherosclerotic lesion area (+80%, P &lt; 0.05). Compared with placebo, testosterone reduced lesion area both in Orx wild-type (WT) mice (by 50%, P &lt; 0.001) and ARKO mice (by 24%, P &lt; 0.05). However, lesion area was larger in testosterone-supplemented ARKO compared with testosterone-supplemented WT mice (+57%, P &lt; 0.05). In WT mice, testosterone reduced the presence of a necrotic core in the plaque (80% among placebo-treated vs. 12% among testosterone-treated mice; P &lt; 0.05), whereas there was no significant effect in ARKO mice (P = 0.20). In conclusion, ARKO mice on apolipoprotein E-deficient background display accelerated atherosclerosis. Testosterone treatment reduced atherosclerosis in both WT and ARKO mice. However, the effect on lesion area and complexity was more pronounced in WT than in ARKO mice, and lesion area was larger in ARKO mice even after testosterone supplementation. These results are consistent with an AR-dependent as well as an AR-independent component of testosterone atheroprotection in male mice.

scholarly journals Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice

2019 ◽  
Vol 61 (3) ◽  
pp. 365-375 ◽  
Author(s):  
Marianne G. Pouwer ◽  
Elsbet J. Pieterman ◽  
Nicole Worms ◽  
Nanda Keijzer ◽  
J. Wouter Jukema ◽  
...  
Keyword(s):  
Triple Therapy ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Lipid Lowering ◽  
Atherosclerosis Progression ◽  
Cholesterol Levels ◽  
Baseline Group ◽  
Current Therapies ◽  
Triple Treatment ◽  
Lesion Severity

Atherosclerosis-related CVD causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab, monoclonal antibodies against cholesterol-regulating proprotein convertase subtilisin/kexin type 9 and angiopoietin-like protein 3, may provide more benefit. We investigated the effect of such lipid-lowering interventions on atherosclerosis in APOE*3-Leiden.CETP mice, a well-established model for hyperlipidemia. Mice were fed a Western-type diet for 13 weeks and thereafter matched into a baseline group (euthanized at 13 weeks) and five groups that received diet alone (control) or with treatment [atorvastatin; atorvastatin and alirocumab; atorvastatin and evinacumab; or atorvastatin, alirocumab, and evinacumab (triple therapy)] for 25 weeks. We measured effects on cholesterol levels, plaque composition and morphology, monocyte adherence, and macrophage proliferation. All interventions reduced plasma total cholesterol (37% with atorvastatin to 80% with triple treatment; all P < 0.001). Triple treatment decreased non-HDL-C to 1.0 mmol/l (91% difference from control; P < 0.001). Atorvastatin reduced atherosclerosis progression by 28% versus control (P < 0.001); double treatment completely blocked progression and diminished lesion severity. Triple treatment regressed lesion size versus baseline in the thoracic aorta by 50% and the aortic root by 36% (both P < 0.05 vs. baseline), decreased macrophage accumulation through reduced proliferation, and abated lesion severity. Thus, high-intensive cholesterol-lowering triple treatment targeting all apoB-containing lipoproteins regresses atherosclerotic lesion area and improves lesion composition in mice, making it a promising potential approach for treating atherosclerosis.

The Rho Family GTPase Cdc42 Regulates Multiple Hematopoietic Stem/Progenitor Cell Functions and Erythropoiesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 32-32
Author(s):  
Lei Wang ◽  
Linda Yang ◽  
Marie–Dominique Filippi ◽  
David A. Williams ◽  
Yi Zheng
Keyword(s):  
Bone Marrow ◽  
Fetal Liver ◽  
Brdu Incorporation ◽  
Low Density ◽  
Actin Assembly ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Rho Family

Abstract The Rho family GTPase Cdc42 has emerged as a key signal transducer in cell regulation. To investigate its physiologic function in hematopoiesis, we have generated mice carrying a gene targeted null allele of cdc42gap, a major negative regulatory gene of Cdc42 and mice with conditional targeted cdc42 allele (cdc42flox/flox). Deletion of the respective gene products in mice was confirmed by PCR genotyping and Western blotting. Low-density fetal liver or bone marrow cells from Cdc42GAP−/− mice displayed ~3 fold elevated Cdc42 activity and normal RhoA, Rac1 or Rac2 activity, indicating that cdc42gap deletion has a specific effect on Cdc42 activity. The Cdc42GAP-deficient hematopoietic stem/progenitor cells (HSC/Ps, Lin−c-Kit+) generated from Cdc42GAP−/− E14.5 fetal liver and the Cdc42−/− HSC/Ps derived by in vitro expression of Cre via a retrovirus vector from Cdc42flox/flox low density bone marrow showed a growth defect in liquid culture that was associated with increased apoptosis but normal cell cycle progression. Cdc42GAP-deficient HSC/Ps displayed impaired cortical F-actin assembly with extended actin protrusions upon exposure to SDF–1 in vitro and a punctuated actin structure after SCF stimulation while Cdc42−/− but not wild type HSC/Ps responded to SDF-1 in inducing membrane protrusions. Both Cdc42−/− and Cdc42GAP−/− HSC/Ps were markedly decreased in adhesion to fibronectin. Moreover, both Cdc42−/− and Cdc42GAP−/− HSC/Ps showed impaired migration in response to SDF-1. These results demonstrate that Cdc42 regulation is essential for multiple HSC/P functions. To understand the in vivo hematopoietic function of Cdc42, we have characterized the Cdc42GAP−/− mice further. The embryos and newborns of homozygous showed a ~30% reduction in hematopoietic organ (i.e. liver, bone marrow, thymus and spleen) cellularity, consistent with the reduced sizes of the animals. This was attributed to the increased spontaneous apoptosis associated with elevated Cdc42/JNK/Bid activities but not to a proliferative defect as revealed by in vivo TUNEL and BrdU incorporation assays. ~80% of Cdc42GAP−/− mice died one week after birth, and the surviving pups attained adulthood but were anemic. Whereas Cdc42GAP−/− mice contained small reduction in the frequency of HSC markers and normal CFU-G, CFU-M, and CFU-GM activities, the frequency of BFU-E and CFU-E were significantly reduced. These results suggest an important role of Cdc42 in erythropoiesis in vivo. Taken together, we propose that Cdc42 is essential for multiple HSC/P functions including survival, actin cytoskeleton regulation, adhesion and migration, and that deregulation of its activity can have a significant impact on erythropoiesis. Cdc42 regulates HSC/P functions and erythropoiesis Genotype/phenotype Apoptosis increase Adhesion decrease Migration decrease F-actin assembly HSC frequency decrease BFU-E, CFU-E decrease The numbers were indicated as fold difference compared with wild type. ND:not determined yet. Cdc42GAP−/− 2.43, p<0.005 0.97, p<0.01 1.01, p<0.01 protrusion (SDF-1); punctruated (SCF) 0.34, p<0.05 0.92, p<0.01; 0.38, p<0 Cdc42−/− 3.68, p<0.005 0.98, p<0.001 3.85, p<0.005 protrusion (SDF-1) ND ND

Abstract 3968: Bone Marrow Derived Growth Differentiation Factor-15 (GDF-15) Protects from Macrophage Accumulation and Effects Atherosclerotic Lesion Stabilisation in Low-Density Lipoprotein Receptor-Null Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Michael R Preusch ◽  
Jens Strelau ◽  
Matthias Baeuerle ◽  
Erwin Blessing ◽  
Marc Bischof ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Peritoneal Macrophages ◽  
Lesion Size ◽  
Fibrous Cap ◽  
Atherosclerotic Lesions ◽  
Density Lipoprotein Receptor ◽  
Macrophage Accumulation

Atherosclerosis is considered to be a chronic inflammatory disease. Macrophages are the prime sources of a variety of inflammatory cytokines and growth factors, which contribute to the initiation and progression of atherosclerotic lesions. The cytokine growth differentiation factor-15 (GDF-15) is a newly discovered member of the transforming growth factor-beta cytokine. GDF-15 participates in vascular inflammation and is mostly expressed by macrophages within the lesions. In this study the impact of GDF-15 deficiency in bone marrow-derived cells on atherogenesis in a mouse model was examined. Bone marrow from GDF15 −/−or GDF-15 +/+ mice was transplanted into lethally irradiated low-density lipoprotein receptor (LDLR−/−) mice (n=38). Twentyfour weeks after administration of a high-fat/high-cholesterol Western type diet atherosclerotic lesion size within the aortic root as well as macrophage content was quantified and compared. In addition features of lesion destabilisation like size of the necrotic core, thinning of the fibrous cap, intra-plaque hemorrhage and calcification were evaluated. In an in-vitro experiment peritoneal macrophages from transplanted mice were harvested and stimulated with tumor necrosis factor alpha (TNFα). Transplantation of GDF-15 −/− bone marrow cells resulted in an enhanced macrophage accumulation within the atherosclerotic lesions (ratio mac/lesion 0.51 versus 0.31; p<0.05) and a significant thinning of the fibrous cap (30.5 versus 48.5 μm; p<0.05). Cell culture experiments demonstrated that macrophages from GDF-15 −/− mice had a much higher induction of ICAM-1 and MCP-1 after stimulation with TNFα in comparison to wildtype peritoneal macrophages. However no difference in lesion size could be reported. Furthermore, there was no difference in plasma lipid levels and body weight. Our data indicates that bone marrow derived GDF-15 protects from macrophage accumulation within atherosclerotic lesions and promotes lesion stabilisation possibly due to inhibition of adhesion molecules and MCP-1.

scholarly journals Participation of the urokinase receptor in neutrophil efferocytosis

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 860-870 ◽  
Author(s):  
Young-Jun Park ◽  
Gang Liu ◽  
Yuko Tsuruta ◽  
Emmanuel Lorne ◽  
Edward Abraham
Keyword(s):  
Cell Migration ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Urokinase Receptor ◽  
Low Density ◽  
Related Protein ◽  
Wild Type ◽  
Arginine Glycine Aspartic Acid

AbstractThe urokinase receptor (uPAR) plays an important role in regulation of fibronolysis, cell migration, and adhesion. In this study, we examined whether uPAR plays a role in modulating efferocytosis of neutrophils. Macrophages from uPAR−/− mice demonstrated enhanced ability to engulf viable wild-type (WT) neutrophils in vitro and in vivo in the lungs. The increased phagocytic activity of uPAR−/− macrophages was abrogated by incubation with soluble uPAR (suPAR), arginine-glycine-aspartic acid (RGD)–containing peptides, or anti-integrin antibodies. There was increased uptake of viable uPAR−/− neutrophils by WT macrophages. Incubation of uPAR−/− neutrophils with suPAR or anti-integrin antibodies diminished uptake by WT macrophages to baseline. Uptake of uPAR−/− neutrophils by uPAR−/− macrophages was not enhanced. However, incubation of uPAR−/− neutrophils or uPAR−/− macrophages, but not both, with suPAR enhanced the uptake of viable uPAR−/− neutrophils by uPAR−/− macrophages. The adhesion of WT neutrophils to uPAR−/− macrophages was higher than to WT macrophages. uPAR−/− neutrophils demonstrated increased adhesion to suPAR, which was abrogated by blocking of low-density lipoprotein related protein and integrins. Expression of uPAR on the surface of apoptotic neutrophils was reduced compared with levels on viable neutrophils. These results demonstrate a novel role for uPAR in modulating recognition and clearance of neutrophils.

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