Effects of Long-term Thrombin Inhibition (Dabigatran Etexilate) on Spontaneous Thrombolytic Activity during the Progression of Atherosclerosis in ApoE−/−–LDLR−/− Double-Knockout Mice

Background: Atherosclerosis is characterized by a hypercoagulable state, during which coagulation and fibrinolytic factors are simultaneously activated. However, details regarding the progression of atherosclerosis remain unknown. Here, we investigated the effects of direct long-term inhibition of thrombin by dabigatran etexilate on atherosclerotic progression in apolipoprotein E–/– and low-density lipoprotein receptor–/– double-knockout mice. Methods: Mice received either standard chow (placebo group) or dabigatran-supplemented chow for 22 weeks. The amount of atherosclerosis was estimated as the ratio of the atherosclerotic area to the total aortic intimal area. Immunohistochemistry was used to examine the expression of Matrix Metalloproteinase-9 (MMP-9), Vascular Endothelial Growth Factor (VEGF), Tissue-Type Plasminogen Activator (t-PA), and Endothelial Nitric Oxide Synthase (eNOS) in atherosclerotic regions. Results: The atherosclerotic area was smaller in the dabigatran group than in the placebo group. Immunohistochemistry revealed decreased expression of MMP-9 and VEGF, but increased expression of eNOS, in the dabigatran group compared with the placebo group. t-PA expression did not differ between the groups. Conclusion: Direct long-term inhibition of thrombin by dabigatran in mice led to a decrease in atherosclerosis progression via decreased expression of MMP-9 and VEGF.

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Hippocampal mossy fiber long-term depression in Grm2/3 double knockout mice

Synapse ◽

10.1002/syn.20923 ◽

2011 ◽

Vol 65 (9) ◽

pp. 945-954 ◽

Cited By ~ 15

Author(s):

Louisa Lyon ◽

Melodie Borel ◽

Miriam CarriÓn ◽

James N.C. Kew ◽

Corrado Corti ◽

...

Keyword(s):

Knockout Mice ◽

Mossy Fiber ◽

Double Knockout ◽

Long Term Depression

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Ticlopidine attenuates progression of atherosclerosis in apolipoprotein E and low density lipoprotein receptor double knockout mice

European Journal of Pharmacology ◽

10.1016/j.ejphar.2006.11.028 ◽

2007 ◽

Vol 556 (1-3) ◽

pp. 129-135 ◽

Cited By ~ 26

Author(s):

Jacek Jawien ◽

Gabor Csanyi ◽

Mariusz Gajda ◽

Lukasz Mateuszuk ◽

Magdalena Lomnicka ◽

...

Keyword(s):

Apolipoprotein E ◽

Knockout Mice ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Lipoprotein Receptor ◽

Double Knockout ◽

Low Density Lipoprotein Receptor ◽

Density Lipoprotein Receptor ◽

Progression Of Atherosclerosis

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081 Analysis and characterization of atherosclerosis in LDLR/GSK3α double knockout mice: Examining the role of glycogen synthase kinase 3 in the progression of atherosclerosis

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2011.07.074 ◽

2011 ◽

Vol 27 (5) ◽

pp. S91

Author(s):

N. Banko ◽

M.I. Khan ◽

Y. Shi ◽

P. Raja ◽

G.H. Werstuck

Keyword(s):

Knockout Mice ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Double Knockout ◽

Progression Of Atherosclerosis

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Abstract 458: Fcgamma Receptor IV Expressed on Inflammatory Cells Drive Diet-induced Atherosclerosis in Hyperlipidemic Mouse Model

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.458 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Branimir Popovic ◽

Doug Feck ◽

Shanmugam Nagarajan

Keyword(s):

T Cells ◽

Mouse Model ◽

Knockout Mice ◽

Inflammatory Responses ◽

Inflammasome Activation ◽

Double Knockout ◽

Arterial Lesions ◽

Apoe Ko Mice ◽

Progression Of Atherosclerosis ◽

Apoe Ko

Objective: Functionally, Fcgamma receptors (FcgRs) can be classified as activating (FcgRI, III, and IV) and inhibitory (FcgRII) receptors. We have reported that combined deficiency of all three activating FcgRs in apoE knockout mice decreased atherosclerosis. In this report, we investigated the independent role of FcgRI and FcgRIV in the progression of atherosclerosis. We investigated the hypothesis that the deficiency of FcgRIV, one of the activating FcgRs, inhibits atherosclerosis in a hypercholesterolemic mouse model. We tested the hypothesis that FcgRI and FcgRIV exacerbate atherosclerosis using apoE-FcgRI dKO and apoE-FcgRIV deficient mice. Approach and Results: ApoE-FcgRI and apoE-FcgRIV double knockout mice (dKO) congenic to the C57BL/6 were generated and atherosclerotic lesions were assessed. Our results show that arterial lesions were not different between apoE-FcgRI dKO and apoE knockout (apoE KO) mice. Interestingly, arterial lesions were significantly decreased in a regular chow or a high-fat diet fed apoE-FcgRIV dKO male and female mice, relative to apoE KO mice. Bone marrow chimeras were used to address the relative contribution of FcgRIV expressed on hematopoietic cells including macrophages and dendritic cell. ApoE KO mice transplanted with apoE-FcgRIV dKO marrow showed significantly reduced arterial lesions relative to recipient mice transplanted with apoE KO marrow. Next, we investigated whether pro-inflammatory response contributed to the pro-atherogenic effect of FcgRIV. Activated CD4+ T cells of apoE-FcgRIV dKO mice showed increased secretion of IL-10, whereas IFN-gamma and IL-17 by T cells were decreased. Interestingly, dendritic cells at the lesion-prone vascular site from apoE-FcgRIV dKO mice induced increased IL-10 secretion by LDL-specific T cells. Moreover, FcgRIV KO and apoE-FcgRIV dKO macrophages showed decreased inflammasome activation as evidenced by decreased IL-1 beta response. Conclusions: Our findings demonstrate that the pro-inflammatory responses initiated by FcgRIV, one of the activating FcgRs, contribute to the progression of atherosclerosis.

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mGluR-Dependent Long-Term Depression Is Associated with Increased Phosphorylation of S6 and Synthesis of Elongation Factor 1A but Remains Expressed in S6K-Deficient Mice

Molecular and Cellular Biology ◽

10.1128/mcb.00201-08 ◽

2008 ◽

Vol 28 (9) ◽

pp. 2996-3007 ◽

Cited By ~ 70

Author(s):

Marcia D. Antion ◽

Lingfei Hou ◽

Helen Wong ◽

Charles A. Hoeffer ◽

Eric Klann

Keyword(s):

Protein Synthesis ◽

Signaling Pathways ◽

Knockout Mice ◽

Metabotropic Glutamate Receptor ◽

Elongation Factor ◽

Double Knockout ◽

Long Term Depression ◽

Group I ◽

Deficient Mice

ABSTRACT Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in the hippocampus requires rapid protein synthesis, which suggests that mGluR activation is coupled to signaling pathways that regulate translation. Herein, we have investigated the signaling pathways that couple group I mGluRs to ribosomal S6 protein phosphorylation and 5′oligopyrimidine tract (5′TOP)-encoded protein synthesis during mGluR-LTD. We found that mGluR-LTD was associated with increased phosphorylation of p70S6 kinase (S6K1) and S6, as well as the synthesis of the 5′TOP-encoded protein elongation factor 1A (EF1A). Moreover, we found that LTD-associated increases in S6K1 phosphorylation, S6 phosphorylation, and levels of EF1A were sensitive to inhibitors of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular signal-regulated kinase (ERK). However, mGluR-LTD was normal in S6K1 knockout mice and enhanced in both S6K2 knockout mice and S6K1/S6K2 double knockout mice. In addition, we observed that LTD-associated increases in S6 phosphorylation were still increased in S6K1- and S6K2-deficient mice, whereas basal levels of EF1A were abnormally elevated. Taken together, these findings indicate that mGluR-LTD is associated with PI3K-, mTOR-, and ERK-dependent alterations in the phosphorylation of S6 and S6K. Our data also suggest that S6Ks are not required for the expression of mGluR-LTD and that the synthesis of 5′TOP-encoded proteins is independent of S6Ks during mGluR-LTD.

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Sugar causes obesity and metabolic syndrome in mice independently of sweet taste

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00529.2019 ◽

2020 ◽

Vol 319 (2) ◽

pp. E276-E290

Author(s):

Ana Andres-Hernando ◽

Masanari Kuwabara ◽

David J. Orlicky ◽

Aurelie Vandenbeuch ◽

Christina Cicerchi ◽

...

Keyword(s):

Metabolic Syndrome ◽

Knockout Mice ◽

De Novo ◽

Sweet Taste ◽

De Novo Lipogenesis ◽

Fibroblast Growth Factor 21 ◽

Relative Role ◽

Double Knockout ◽

Metabolic Outcome

Intake of sugars, especially the fructose component, is strongly associated with the development of obesity and metabolic syndrome, but the relative role of taste versus metabolism in driving preference, intake, and metabolic outcome is not fully understood. We aimed to evaluate the preference for sweet substances and the tendency to develop metabolic syndrome in response to these sugars in mice lacking functional taste signaling [P2X2 (P2X purinoreceptor 2)/P2X3 (P2X purinoreceptor 3) double knockout mice (DKO)] and mice unable to metabolize fructose (fructokinase knockout mice). Of interest, our data indicate that despite their inability to taste sweetness, P2X2/3 DKO mice still prefer caloric sugars (including fructose and glucose) to water in long-term testing, although with diminished preference compared with control mice. Despite reduced intake of caloric sugars by P2X2/3 DKO animals, the DKO mice still show increased levels of the sugar-dependent hormone FGF21 (fibroblast growth factor 21) in plasma and liver. Despite lower sugar intake, taste-blind mice develop severe features of metabolic syndrome due to reduced sensitivity to leptin, reduced ability to mobilize and oxidize fats, and increased hepatic de novo lipogenesis. In contrast to P2X2/3 DKO and wild-type mice, fructokinase knockout mice, which cannot metabolize fructose and are protected against fructose-induced metabolic syndrome, demonstrate reduced preference and intake for all fructose-containing sugars tested but not for glucose or artificial sweeteners. Based on these observations, we conclude that sugar can induce metabolic syndrome in mice independently of its sweet properties. Furthermore, our data demonstrate that the metabolism of fructose is necessary for sugar to drive intake and preference in mice.

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Understanding the progression of atherosclerosis through gene profiling and co-expression network analysis in Apob tm2Sgy Ldlr tm1Her double knockout mice

Genomics ◽

10.1016/j.ygeno.2016.04.007 ◽

2016 ◽

Vol 107 (6) ◽

pp. 239-247 ◽

Cited By ~ 6

Author(s):

Vrushali Deshpande ◽

Ankit Sharma ◽

Rupak Mukhopadhyay ◽

Lakshmi Narasimha Rao Thota ◽

Madankumar Ghatge ◽

...

Keyword(s):

Network Analysis ◽

Knockout Mice ◽

Gene Profiling ◽

Double Knockout ◽

Progression Of Atherosclerosis

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Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice

Biochemical Journal ◽

10.1042/bj20112197 ◽

2012 ◽

Vol 443 (3) ◽

pp. 829-839 ◽

Cited By ~ 29

Author(s):

Nam Ho Jeoung ◽

Yasmeen Rahimi ◽

Pengfei Wu ◽

W. N. Paul Lee ◽

Robert A. Harris

Keyword(s):

Knockout Mice ◽

Pyruvate Dehydrogenase ◽

Ketone Bodies ◽

Pyruvate Dehydrogenase Complex ◽

Pyruvate Dehydrogenase Kinase ◽

Flux Analysis ◽

Double Knockout ◽

Complex Activity ◽

Fasted State

The importance of PDHK (pyruvate dehydrogenase kinase) 2 and 4 in regulation of the PDH complex (pyruvate dehydrogenase complex) was assessed in single- and double-knockout mice. PDHK2 deficiency caused higher PDH complex activity and lower blood glucose levels in the fed, but not the fasted, state. PDHK4 deficiency caused similar effects, but only after fasting. Double deficiency intensified these effects in both the fed and fasted states. PDHK2 deficiency had no effect on glucose tolerance, PDHK4 deficiency produced only a modest effect, but double deficiency caused a marked improvement and also induced lower insulin levels and increased insulin sensitivity. In spite of these beneficial effects, the double-knockout mice were more sensitive than wild-type and single-knockout mice to long-term fasting, succumbing to hypoglycaemia, ketoacidosis and hypothermia. Stable isotope flux analysis indicated that hypoglycaemia was due to a reduced rate of gluconeogenesis and that slightly more glucose was converted into ketone bodies in the double-knockout mice. The findings establish that PDHK2 is more important in the fed state, PDHK4 is more important in the fasted state, and survival during long-term fasting depends upon regulation of the PDH complex by both PDHK2 and PDHK4.

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Altered Hippocampal Synaptic Plasticity in the Fmr1 Gene Family Knockout Mouse Models

Journal of Neurophysiology ◽

10.1152/jn.90558.2008 ◽

2009 ◽

Vol 101 (5) ◽

pp. 2572-2580 ◽

Cited By ~ 62

Author(s):

Jing Zhang ◽

Lingfei Hou ◽

Eric Klann ◽

David L. Nelson

Keyword(s):

Protein Synthesis ◽

Mental Retardation ◽

Synaptic Plasticity ◽

Knockout Mice ◽

Fragile X ◽

Fmr1 Gene ◽

Double Knockout ◽

Fragile X Mental Retardation ◽

Presynaptic Plasticity

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. The syndrome results from the absence of the fragile X mental retardation protein (FMRP), which is encoded by the fragile X mental retardation 1 ( FMR1) gene. FMR1 and its two paralogs, fragile X–related genes 1 and 2 ( FXR1 and -2), form the Fmr1 gene family. Here, we examined long-lasting synaptic plasticity in Fmr1 knockout, Fxr2 knockout, and Fmr1/ Fxr2 double knockout mice. We found that metabotropic glutamate receptor–dependent long-term depression (mGluR-LTD) in the hippocampus was affected in Fmr1 knockout, Fxr2 knockout, and Fmr1/ Fxr2 double knockout mice at young ages (4–6 wk old). In addition, Fmr1/ Fxr2 double knockout mice showed significant deficiencies relative to either Fmr1 or Fxr2 knockout mice in baseline synaptic transmission and short-term presynaptic plasticity, suggesting FMRP and FXR2P may contribute in a cooperative manner to pathways regulating presynaptic plasticity. However, compared with wild-type littermates, late-phase long-term potentiation (L-LTP) was unaltered in all knockout mice at 4–6 mo of age. Interestingly, although Fmr1/ Fxr2 double knockout mice exhibited a more robust enhancement in mGluR-LTD compared with that in Fmr1 knockout mice, Fxr2 knockout mice exhibited reduced mGluR-LTD. Furthermore, unlike Fmr1 knockout mice, mGluR-LTD in Fxr2 knockout mice required new protein synthesis, whereas mGluR-LTD in Fmr1/ Fxr2 double knockout mice was partially dependent on protein synthesis. These results indicated that both FMRP and FXR2P function in synaptic plasticity and that they likely operate in related but independent pathways.

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