Abstract 623: Role Of Cd73-derived Adenosine In Atherosclerosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Anja Buchheiser ◽  
Barbara Emde ◽  
Jens W Fischer ◽  
Jürgen Schrader
Keyword(s):  
Thoracic Aorta ◽  
Double Mutant ◽  
Vascular Inflammation ◽  
Mutant Mice ◽  
Matrix Composition ◽  
Atherosclerotic Plaques ◽  
Chow Diet ◽  
Double Knockout ◽  
Aortic Sinus ◽  
Atherosclerotic Lesions

We recently reported that mice with targeted deletion of ecto-5′-nucleotidase (CD73) are characterized by enhanced platelet activation and increased adherence of monocytes to the endothelium. Wire-induced injury of the carotid artery resulted in enhanced neointima formation associated with increased macrophage content and VCAM-1 expression in CD73−/−mice. In order to study a possible modulation of atherogenesis and vascular inflammation by CD73-derived adenosine, we generated ApoE−/−/CD73−/− double mutant mice. Quantification and characterisation of atherosclerotic lesions was performed in WT, ApoE−/−, and ApoE−/− / CD73−/− mice on chow diet after 6 and 12 month, respectively, by macroscopic analysis of the descending thoracic aorta after oil red staining and by histological stainings for cholesterol, hyaloronic acid, and collagen in cryo sections of the aortic sinus. Immunohistological analysis of lesion morphology included primary antibodies for ICAM-1, VCAM-1, CD4, CD73, and CD11b. Determination of the plaque score by oil red staining revealed enhanced development of atherosclerotic lesions over the entire thoracic aorta after 6 month in the double mutant compared with ApoE−/− (2.5-fold increased, n=8, P<0.05). Atherosclerotic plaques in the aortic sinus were substantially enlarged as compared to ApoE−/− mice. Changes in extracellular matrix composition were not detected. However, we found enhanced VCAM-1 expression in ApoE−/−/CD73−/− mice after 6 month, which was accompanied by an increased infiltration of monocytes and macrophages but unchanged T-cells. We also noted that in atherosclerotic plaques of ApoE−/− mice the expression and activity of CD73 was significantly increased compared to WT. Measurements of cytokines in plasma support the notion of an increased inflammatory state in the double knockout. Interestingly, after 12 months all double mutant mice showed multiple scattered myocardial infarcts associated with myocardial hypertrophy and fibrosis. Our findings demonstrate that CD73-derived adenosine acts as an endogenous modulator protecting against chronic vascular inflammation and monocyte recruitment. Thus in the murine model, extracellular adenosine appears to limit the progression of atherosclerosis.

ICAM-1 deficiency reduces atherosclerotic lesions in double knockout mice (apo-E−/−/ICAM-1−/−) fed a fat or a chow diet

1999 ◽  
Vol 144 ◽  
pp. 166-167
Author(s):  
M.C. Bourdillon ◽  
C. Covacho ◽  
R.N. Poston ◽  
E. Chignier ◽  
G. Canard ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Chow Diet ◽  
Double Knockout ◽  
Atherosclerotic Lesions ◽  
Apo E

ICAM-1 deficiency reduces atherosclerotic lesions in double knockout mice (Apo-E−/−/ICAM-I−/−) fed a fat or a chow diet

1999 ◽  
Vol 144 ◽  
pp. 94 ◽  
Author(s):  
M.C. Bourdillon ◽  
C. Covacho ◽  
R.N. Poston ◽  
E. Chignier ◽  
G. Canard ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Chow Diet ◽  
Double Knockout ◽  
Atherosclerotic Lesions ◽  
Apo E

scholarly journals ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE − /− /ICAM-1 − /− ) Fed a Fat or a Chow Diet

2000 ◽  
Vol 20 (12) ◽  
pp. 2630-2635 ◽  
Author(s):  
Marie-Claude Bourdillon ◽  
Robin N. Poston ◽  
Chantal Covacho ◽  
Elza Chignier ◽  
Giampiero Bricca ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Chow Diet ◽  
Double Knockout ◽  
Atherosclerotic Lesions

scholarly journals Cyclin D2 and p27 Are Tissue-Specific Regulators of Tumorigenesis in Inhibin α Knockout Mice

2003 ◽  
Vol 17 (10) ◽  
pp. 2053-2069 ◽  
Author(s):  
Kathleen H. Burns ◽  
Julio E. Agno ◽  
Piotr Sicinski ◽  
Martin M. Matzuk
Keyword(s):  
Cell Cycle ◽  
Sertoli Cell ◽  
Knockout Mice ◽  
Double Mutant ◽  
Adrenal Tumor ◽  
Tumor Development ◽  
Mutant Mice ◽  
Cyclin D2 ◽  
Double Knockout ◽  
Single Knockout

Abstract Inhibins are heterodimeric (α:βA and α:βB) endocrine, paracrine, and autocrine factors of the TGFβ superfamily that are produced predominantly by ovarian granulosa cells in females and testicular Sertoli cells in males. Control of granulosa and Sertoli cell proliferation is lost in the inhibin α (Inhα) knockout mouse model, leading to gonadotropin-dependent gonadal tumors of the granulosa/Sertoli cell lineage in both females and males. Castrate Inhα knockout mice develop sex steroidogenic tumors of the adrenal cortex. Physiological control of granulosa/Sertoli cell cycle progression depends on p27Kip1 and cyclin D2, which function in the G1 → S phase transition. To study the cell cycle-regulatory factors involved in ovarian, testicular, and adrenal tumor development in vivo, we have bred Inhα mutant mice to mice with targeted disruptions of the p27 and cyclin D2 genes. Our previous studies demonstrated that inhibins act cooperatively with p27 to negatively regulate granulosa cell proliferation, as double mutant mice lacking inhibins and p27 develop and succumb to ovarian tumors more rapidly than Inhα knockout mice. Here, we report that cyclin D2 antagonizes this inhibition and is key in promoting gonadal growth and tumor development, and tumor development is markedly suppressed in double-mutant mice. We found that double-knockout females lacking cyclin D2 and Inhα lived longer than mice lacking inhibins alone; the majority of these double-knockout mice lived longer than 17 wk, as opposed to inhibin α single-knockout females with 50% survival at between 12 and 13 wk of age. Moreover, 95% of inhibin α knockout males succumb to testicular tumor development by 12 wk of age, whereas double knockouts were protected from early signs of tumor development and had a 50% survival of 40 wk. Interestingly, the results of these studies reflect tissue-specific consequences of loss of these cell cycle regulators. In castrate mice, loss of p27 has little effect on adrenal cortical tumor progression in the absence of inhibins, whereas loss of cyclin D2 prolongs the lifespan of cyclin D2, Inhα double knockouts. After gonadectomy, 50% of cyclin D2, Inhα double-knockout males live to more than 46 wk of age, 10 wk longer than 50% of littermates lacking only inhibins. Similarly, 50% of female cyclin D2, inhibin α double knockouts live to 47 wk of age before succumbing to adrenal tumor development, in contrast to the 50% survival of Inhα single-knockout females at between 27 and 28 wk. Thus, identification of genetic modifiers of the Inhα knockout tumor phenotype has led us to a better appreciation of how specific components of the cell cycle machinery contribute to tumorigenesis in the ovary, testis, and adrenal gland.

Abstract 18838: Inhibition and Genetic Deficiency of Trem-1 Receptor Reduces Development of Experimental Atherosclerosis in Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jérémie Joffre ◽  
Stephane Potteaux ◽  
Amir Boufenzer ◽  
Xavier Loyer ◽  
Safa Mellak ◽  
...  
Keyword(s):  
Oxidized Ldl ◽  
Experimental Atherosclerosis ◽  
Lesion Size ◽  
Atherosclerotic Plaques ◽  
Chow Diet ◽  
Chimeric Mice ◽  
Marrow Graft ◽  
Aortic Sinus ◽  
Stable Plaque

Introduction: Innate immunity, particularly monocytes / macrophages and neutrophils, play a major role in the development and the complications of atherosclerosis. TREM-1 is a recently discovered receptor expressed by myeloid cells that amplifies the inflammatory response by increasing chemokines and pro inflammatory cytokines production. The aim of this study was to determine the role of TREM-1 in experimental atherosclerosis. Methods and results: TREM-1 is not present in healthy artery but is expressed (mRNA and protein) in human carotid atherosclerotic plaques, mainly by macrophages. 8 week-old Ldlr-/ - mice were lethally irradiated and transplanted with a bone marrow graft Trem-1 + / + or Trem-1-/ - and put on a fat diet (FD) during 14 weeks. Cholesterol levels were not different between the two groups. In Ldlr-/-/Trem-1-/ - chimeric mice, we observed a 60% reduction of the lesion size in the aortic sinus (120100 ± 139600 vs 479116 ± 70229 μm2, P = 0.006) and a 49% reduction on the thoracic aorta (9.5 ± 2.2 vs 4.8 ± 1.6% surface ratio, P = 0.02). In Ldlr-/-/Trem-1-/- chimeric mice, plaques showed a significant decrease in macrophage infiltration (MOMA +, P=0.029) and a reduction in necrotic core size (Masson’s trichrome, P=0.003). In vitro, splenocytes from Ldlr-/-Trem-1-/- stimulated by oxidized LDL produced less IL-12 (ELISA) than control chimeric splenocytes (126 ±104 vs 1185 ± 795 pg/ml, P = 0.001). We have developed a dodecapeptide (LR-12) wich inhibits TREM-1 binding to its endogenous ligand. Apoe-/- mice were treated by daily intraperitoneal injections of LR-12 (100μg) or scramble peptide during 4 weeks. We observed that LR-12 treatment reduced atherosclerosis development on a chow diet (-30%, P <0.05) and on a high fat diet (-42%, P = 0.005). Conclusion: TREM-1 is expressed in human and mouse atherosclerotic plaques. TREM-1 genetic invalidation and pharmacological inhibition reduce the development of atherosclerosis and induce a more stable plaque phenotype.

Abstract 646: The Paradoxical Role of TREM-Like 1 in Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Marieli Gonzalez ◽  
Carlos J Collado ◽  
Fiorella Reyes ◽  
Mayra Báez ◽  
Anthony V Washington
Keyword(s):  
Lipid Metabolism ◽  
Platelet Reactivity ◽  
Vascular Inflammation ◽  
Compositional Analysis ◽  
Lesion Size ◽  
Atherogenic Diet ◽  
Double Knockout ◽  
Aortic Sinus ◽  
Cell Content ◽  
Atherosclerosis Progression

Atherosclerosis is a chronic inflammatory process of the vessel wall driven by an inflammatory state caused by the involvement of different cell populations, including platelets. The receptor Triggering Receptor Expressed on Myeloid Cells (TREM)-like transcript (TLT)-1 is prepacked in platelet α-granules and brought to the surface upon activation. TLT-1 has both membrane-bound and soluble forms (sTLT-1) and the latter has been found to enhance platelet activation as well as platelet-endothelial cell interactions. TLT-1 null mice (treml1-/-) have reduced platelet aggregation, are significantly more susceptible to lipopolysaccharide challenge compared to their wild type counterparts, and accordingly, hemorrhage in response to an acute inflammatory challenge. These results suggest that TLT-1 is a key regulatory molecule in the interface between hemostatic and inflammatory mechanisms and in light of this, we hypothesized that TLT-1 plays an important role in atherosclerosis progression. To address this, we generated apoE-/-/treml1-/- double knockout mice [DKO]. We found that DKO mice fed an atherogenic diet (HFD) showed significantly increased weight gain when compared to apoE-/-. Accordingly, DKO mice showed increased total cholesterol and triglycerides compared to controls. Surprisingly, assessment of lesion size revealed that DKO mice have significantly smaller lesions in the aortic sinus at four and 12 weeks after HFD compared to apoE-/-. At 20 weeks, lesion differences are no longer significant, but compositional analysis revealed that DKO atherosclerotic lesions are less vulnerable as seen by decreased lesion calcification and increased smooth muscle cell content. Furthermore, q-rtPCR analysis of atherosclerosis-related genes revealed that TLT-1 differentially affects genes related to lipid metabolism (apo AI and B) and vascular inflammation (thrombospondin 4, PAI-1 and VGFR-2). While our data suggests that the smaller lesion size may be explained by lower platelet reactivity, differences in cholesterol levels suggest altered lipid metabolism which is supported by our metabolomics studies (González, M. et.al). Taken together TLT-1 plays a dual role in the progression of atherosclerosis.

Abstract 13405: Genetic Deletion of Stimulator of Interferon Genes Attenuates Atherogenesis in Apolipoprotein E-deficient Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Phuong T Pham ◽  
Daiju Fukuda ◽  
Masataka Sata
Keyword(s):  
Innate Immunity ◽  
Apolipoprotein E ◽  
Aortic Arch ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Vascular Inflammation ◽  
Atherosclerotic Plaques ◽  
Atherosclerotic Lesions ◽  
Gene And Protein Expression ◽  
Inflammatory Molecules

Introduction: Recent studies show the contribution of innate immunity system to the pathogenesis of inflammatory diseases, including atherosclerosis. Stimulation of interferon genes (STING), originally known as a cytosolic DNA sensor, recognizes cytosolic DNA fragments, activating innate immunity. Here, we investigated whether STING contributes to the development of vascular inflammation and atherogenesis in apolipoprotein E-deficient (Apoe –/– ) mice. Methods and Results: The expression of STING increased in the atherosclerotic aorta in both gene and protein expression levels. STING-deficient Apoe –/– (STING –/– Apoe –/– ) mice reduced atherosclerotic lesions in the aortic arch ( P <0.05), along with the reduction of lipid and macrophage accumulation in atherosclerotic plaques ( P <0.05, respectively), and inflammatory molecule expression in the aorta compared with those in Apoe –/– mice after 20 weeks on a western-type diet. Also, pharmacologic blockade of STING in Apoe –/– mice for 12 weeks treatment attenuated atherogenesis in the aortic arch ( P <0.05), reduced the accumulation of lipid in atherosclerotic plaques ( P <0.05) with no alteration of metabolic parameters. Restoration of STING in bone marrow in STING –/– Apoe –/– mice promoted atherogenesis ( P <0.05), lipid deposition ( P <0.05), and vascular inflammation. cGAMP, a specific STING agonist, or mitochondrial DNA extracted from macrophages promoted expression of inflammatory molecules more effectively in Apoe -/- macrophages than in STING –/– Apoe –/– macrophages, while C-176, a specific STING inhibitor, attenuated these inflammatory responses. The results of western blotting showed the involvement of NF-κB and IRF-3 signaling in STING-associated vascular inflammation and macrophage activation. Furthermore, in humans, STING expression was confirmed in atherosclerotic lesions in the carotid artery. Conclusion: STING signaling activates macrophages, promotes vascular inflammation and atherosclerosis in Apoe -/- mice. Our results suggest that STING may serve as a potential therapeutic target for atherosclerosis.

scholarly journals The Ovary Is an Alternative Site of Origin for High-Grade Serous Ovarian Cancer in Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (6) ◽  
pp. 1975-1981 ◽  
Author(s):  
Jaeyeon Kim ◽  
Donna M. Coffey ◽  
Lang Ma ◽  
Martin M. Matzuk
Keyword(s):  
Ovarian Cancer ◽  
Double Mutant ◽  
P53 Mutation ◽  
Mutant Mice ◽  
Serous Carcinoma ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Fallopian Tubes ◽  
Double Knockout ◽  
Triple Mutant

Abstract Although named “ovarian cancer,” it has been unclear whether the cancer actually arises from the ovary, especially for high-grade serous carcinoma (HGSC), also known as high-grade serous ovarian cancer, the most common and deadliest ovarian cancer. In addition, the tumor suppressor p53 is the most frequently mutated gene in HGSC. However, whether mutated p53 can cause HGSC remains unknown. In this study, we bred a p53 mutation, p53R172H, into conditional Dicer-Pten double-knockout (DKO) mice, a mouse model duplicating human HGSC, to generate triple-mutant (TKO) mice. Like DKO mice, these TKO mice develop metastatic HGSCs originating from the fallopian tube. Unlike DKO mice, however, even after fallopian tubes are removed in TKO mice, ovaries alone can develop metastatic HGSCs, indicating that a p53 mutation can drive HGSC arising from the ovary. To confirm this, we generated p53R172H-Pten double-mutant mice, one of the genetic control lines for TKO mice. As anticipated, these double-mutant mice also develop metastatic HGSCs from the ovary, verifying the HGSC-forming ability of ovaries with a p53 mutation. Our study therefore shows that ovaries harboring a p53 mutation, as well as fallopian tubes, can be a distinct tissue source of high-grade serous ovarian cancer in mice.

scholarly journals p50–NF-κB Complexes Partially Compensate for the Absence of RelB: Severely Increased Pathology in p50−/−relB−/−Double-knockout Mice

1997 ◽  
Vol 185 (7) ◽  
pp. 1359-1370 ◽  
Author(s):  
Falk Weih ◽  
Stephen K. Durham ◽  
Debra S. Barton ◽  
William C. Sha ◽  
David Baltimore ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Double Mutant ◽  
Family Members ◽  
Premature Death ◽  
Mutant Mice ◽  
Mrna Levels ◽  
Double Knockout ◽  
Inflammatory Phenotype ◽  
Inflammatory Infiltrates ◽  
Disease Free

RelB-deficient mice (relB−/−) have a complex phenotype including multiorgan inflammation and hematopoietic abnormalities. To examine whether other NF-κB/Rel family members are required for the development of this phenotype or have a compensatory role, we have initiated a program to generate double-mutant mice that are deficient in more than one family member. Here we report the phenotypic changes in relB−/− mice that also lack the p50 subunit of NFκB (p50−/−). The inflammatory phenotype of p50−/−relB−/− double-mutant mice was markedly increased in both severity and extent of organ involvement, leading to premature death within three to four weeks after birth. Double-knockout mice also had strongly increased myeloid hyperplasia and thymic atrophy. Moreover, B cell development was impaired and, in contrast to relB−/− single knockouts, B cells were absent from inflammatory infiltrates. Both p50−/− and heterozygous relB−/+ animals are disease-free. In the absence of the p50, however, relB−/+ mice (p50−/−relB−/+) had a mild inflammatory phenotype and moderate myeloid hyperplasia. Neither elevated mRNA levels of other family members, nor increased κB-binding activities of NF-κB/Rel complexes could be detected in single- or double-mutant mice compared to control animals. These results indicate that the lack of RelB is, in part, compensated by other p50-containing complexes and that the “classical” p50-RelA–NF-κB activity is not required for the development of the inflammatory phenotype.

Spontaneous Atherosclerotic Lesions in TREM-Like Transcript-1 Deficient Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3312-3312
Author(s):  
Marieli Gonzalez ◽  
Fiorella Reyes ◽  
Deborah Marrero ◽  
A. Valance Washington
Keyword(s):  
Vessel Wall ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Atherogenic Diet ◽  
Chow Diet ◽  
Aortic Sinus ◽  
Platelet Surface ◽  
Atherosclerosis Progression ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels

Abstract Abstract 3312 It is well known that platelets, aside from regulating hemostasis, play an important role in inflammation-associated conditions like sepsis, viral infections, and atherosclerosis. In the latter, platelets not only form occlusive thrombi at lesions, but also play a role in the initiation of the disease by depositing activating molecules such as cytokines on the developing plaque. Although the mechanism by which platelet aggregation leads to occlusion is well-defined, the role of platelets in lesion initiation and progression is poorly understood and thus remains a gap in our knowledge. TLT-1 (Triggering Receptor Expressed in Myeloid cells (TREM)-like transcript-1) is a receptor exclusively found on megakarocytes and platelets that has a demonstrated effect in inflammatory responses. Upon platelet activation, TLT-1 is moved to the platelet surface along with p-selectin from the α-granules. Studies using the 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 and therefore should play a role in the development of atherosclerosis. Our original hypothesis was that evaluation of atherosclerosis lesions in the treml1−/− mouse would demonstrate fewer lesions and hence, a similar phenotype as the psel−/− mouse. Evaluation of 50 week old mice fed a chow diet surprisingly revealed spontaneous lesions in C57Bl/6 treml1−/− mice. Subsequent evaluation of cholesterol levels in treml1−/−mice on an atherogenic diet for four weeks demonstrated that they have significantly higher cholesterol levels when compared to WT mice. To evaluate atherosclerosis progression in TLT-1 deficiency, we developed the apoE−/−/treml1−/− double knockout mice and assessed lesion development after a four weeks atherogenic diet. Our results demonstrate that double null mice have exacerbated lesions when compared to the apoE −/− mice. Accordingly, 50 week old double null mice fed a chow diet also have larger atherosclerotic lesions in the aortic sinus than apoE −/− mice. These results clearly support a role for TLT-1 in dampening the progression of atherosclerosis. Current data from our laboratory suggest that TLT-1 may affect leukocyte function, therefore based on our model that TLT-1 deficiency leads to a heighted inflammatory state we hypothesized that treml1−/− mice will demonstrate greater leukocyte recruitment into the injured vessel wall, leading to greater deposition of factors that recruit more platelets and macrophages that later become foam cells. To delineate the mechanism by which TLT-1 affects atherosclerosis progression, we have evaluated neutrophil and monocyte infiltration into the vessel wall of the aortic sinus after four weeks atherogenic diet. The current state of our investigation is reported here. Disclosures: No relevant conflicts of interest to declare.

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