scholarly journals The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE–Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype

2021 ◽  
Vol 22 (18) ◽  
pp. 9772
Author(s):  
Anna Kiepura ◽  
Kamila Stachyra ◽  
Anna Wiśniewska ◽  
Katarzyna Kuś ◽  
Klaudia Czepiel ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Knockout Mice ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Molecular Methods ◽  
Prolonged Treatment ◽  
Macrophage Phenotype ◽  
Mice Model ◽  
Significant Amelioration ◽  
Apoe Knockout Mice

Background: Over the past few years, a better understanding of the biology of G-protein coupled receptors (GPRs) has led to the identification of several receptors as novel targets for free fatty acids (FFAs). FFAR4 has received special attention in the context of chronic inflammatory diseases, including atherosclerosis, obesity and NAFLD, through to its anti-inflammatory effect. Methods: The present study investigates the influence of prolonged treatment with TUG-891-FFAR4 agonist on the development of atherosclerosis plaque in apoE-knockout mice, using morphometric and molecular methods. Results: TUG-891 administration has led to the reduction of atherosclerotic plaque size and necrotic cores in an apoE-knockout mice model. TUG-891-treated mice were administered subcutaneously at a dose of 20 mg/kg three times a week for 4 months. The FFAR4 agonist reduced the content of pro-inflammatory M1-like macrophages content in atherosclerotic plaques, as evidenced by immunohistochemical phenotyping and molecular methods. In atherosclerotic plaque, the population of smooth muscle cells increased as evidenced by α-SMA staining. We observed changes in G-CSF and eotaxin markers in the plasma of mice; changes in the levels of these markers in the blood may be related to macrophage differentiation. Importantly, we observed a significant increase in M2-like macrophage cells in atherosclerotic plaque and peritoneum. Conclusions: Prolonged administration of TUG-891 resulted in significant amelioration of atherogenesis, providing evidence that the strategy based on macrophage phenotype switching toward an M2-like activation state via stimulation of FFAR4 receptor holds promise for a new approach in the prevention or treatment of atherosclerosis.

scholarly journals Angiotensin II induces extracellular matrix metalloproteinase inducer expression via an AT1R dependent pathway in aortic atherosclerotic plaque in apolipoprotein E knockout mice

2011 ◽  
Vol 13 (1) ◽  
pp. 67-75 ◽  
Author(s):  
Li-xia Yang ◽  
Zhi-hua Yang ◽  
Rui-wei Guo ◽  
Jin-shan Ye ◽  
Hong Liu
Keyword(s):  
Extracellular Matrix ◽  
Angiotensin Ii ◽  
Matrix Metalloproteinase ◽  
Protein Expression ◽  
Atherosclerotic Plaque ◽  
Knockout Mice ◽  
Ang Ii ◽  
Extracellular Matrix Metalloproteinase Inducer ◽  
Apolipoprotein E Knockout Mice ◽  
Apoe Knockout Mice

The pathogenesis of acute coronary syndrome is rupture of vulnerable plaque. Extracellular matrix metalloproteinase inducer (EMMPRIN) is reported to have a important role in the destabilization of atheroma. Objectives: this investigation examined the effect of angiotensin II (Ang II) on EMMPRIN expression in atherosclerotic plaques in ApoE knockout mice. Methods: ApoE knockout mice were fed a high fat diet to establish an atherosclerosis model then intervention was made with Ang II and valsartan. EMMPRIN gene and its protein expression were measured by real-time PCR immunohistochemistry, and Western blot. Results: EMMPRIN gene and protein expression intervened with Ang II were significantly increased; valsartan could inhibit the effect of Ang II. Conclusion: Ang II up-regulated EMMPRIN expression in atherosclerotic plaque via AT1R, and valsartan could inhibit the effect of Ang II.

Rosiglitazone promotes atherosclerotic plaque stability in fat-fed ApoE-knockout mice

2008 ◽  
Vol 590 (1-3) ◽  
pp. 297-302 ◽  
Author(s):  
Mingxue Zhou ◽  
Hao Xu ◽  
Lin Pan ◽  
Jianyan Wen ◽  
Wenqiang Liao ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Knockout Mice ◽  
Plaque Stability ◽  
Apoe Knockout Mice

scholarly journals p16INK4a deficiency promotes IL-4–induced polarization and inhibits proinflammatory signaling in macrophages

Blood ◽  
2011 ◽  
Vol 118 (9) ◽  
pp. 2556-2566 ◽  
Author(s):  
Céline Cudejko ◽  
Kristiaan Wouters ◽  
Lucía Fuentes ◽  
Sarah Anissa Hannou ◽  
Charlotte Paquet ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Suppressor Gene ◽  
In Vivo Model ◽  
Macrophage Phenotype ◽  
Age Related ◽  
Increased Risk ◽  
Increased Sensitivity

Abstract The CDKN2A locus, which contains the tumor suppressor gene p16INK4a, is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMφ) or alternatively (AAMφ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16INK4a deficiency (p16−/−) modulates the macrophage phenotype. Transcriptome analysis revealed that p16−/− BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4–induced macrophage polarization. In line with this observation, p16−/− BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16−/− BM displayed higher hepatic AAMφ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMφ phenotype skewing. Surprisingly, p16−/− BMDMs did not display increased IL-4–induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)–induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16INK4a as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.

scholarly journals Contribution of Thrombospondin-1 and -2 to Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Qiang Li ◽  
Xiaoxiao Fu ◽  
Jiang Yuan ◽  
Shu Han
Keyword(s):  
T Regulatory Cells ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Endothelial Permeability ◽  
M2 Macrophage ◽  
Vascular Endothelial ◽  
Macrophage Phenotype ◽  
Thrombospondin 1

Thrombospondin (TSP) proteins have been shown to impact T-cell adhesion, migration, differentiation, and apoptosis. Thrombospondin-1 (TSP-1) is specifically upregulated in several inflammatory diseases and can effectively promote lipopolysaccharide- (LPS-) induced inflammation. In contrast, thrombospondin-2 (TSP-2) has been associated with activation of “anti-inflammatory” T-regulatory cells (Tregs). In this study, we investigated the effects of both TSP-1 and TSP-2 overexpression on macrophage polarization and activation in vitro and in vivo. We analyzed the effects of TSP-1 and TSP-2 on inflammation, vascular endothelial permeability, edema, ultrastructural morphology, and apoptosis in lung tissues of an ARDS mouse model and cultured macrophages. Our results demonstrated that TSP-2 overexpression effectively attenuated LPS-induced ARDS in vivo and promoted M2 macrophage phenotype polarization in vitro. Furthermore, TSP-2 played a role in regulating pulmonary vascular barrier leakage by activating the PI3K/Akt pathway. Overall, our findings indicate that TSP-2 can modulate inflammation and could therefore be a potential therapeutic target against LPS-induced ARDS.

ASSA14-03-33 Over restrictive salt diet promotes atherosclerotic plaque growth and instability through PCSK9 in ApoE knockout mice

Heart ◽  
2014 ◽  
Vol 101 (Suppl 1) ◽  
pp. A20.2-A21
Author(s):  
N Zhu ◽  
C Yan ◽  
X Zhang ◽  
X Zhao ◽  
Y Zhang ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Knockout Mice ◽  
Salt Diet ◽  
Apoe Knockout Mice ◽  
Plaque Growth

Long-Term Exercise Stabilizes Atherosclerotic Plaque in ApoE Knockout Mice

2009 ◽  
Vol 41 (12) ◽  
pp. 2128-2135 ◽  
Author(s):  
MAXIME PELLEGRIN ◽  
CAROLE MIGUET-ALFONSI ◽  
KARIMA BOUZOURENE ◽  
JEAN-FRANÇOIS AUBERT ◽  
VALÉRIE DECKERT ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Knockout Mice ◽  
Apoe Knockout Mice

Mechanobiology of Macrophages: How Physical Factors Coregulate Macrophage Plasticity and Phagocytosis

2019 ◽  
Vol 21 (1) ◽  
pp. 267-297 ◽  
Author(s):  
Nikhil Jain ◽  
Jens Moeller ◽  
Viola Vogel
Keyword(s):  
Inflammatory Diseases ◽  
Apoptotic Cell ◽  
Macrophage Polarization ◽  
New Drugs ◽  
Physical Factors ◽  
Macrophage Phenotype ◽  
Pathological Conditions ◽  
Macrophage Plasticity ◽  
And Function ◽  
Made In

In addition to their early-recognized functions in host defense and the clearance of apoptotic cell debris, macrophages play vital roles in tissue development, homeostasis, and repair. If misregulated, they steer the progression of many inflammatory diseases. Much progress has been made in understanding the mechanisms underlying macrophage signaling, transcriptomics, and proteomics, under physiological and pathological conditions. Yet, the detailed mechanisms that tune circulating monocytes/macrophages and tissue-resident macrophage polarization, differentiation, specification, and their functional plasticity remain elusive. We review how physical factors affect macrophage phenotype and function, including how they hunt for particles and pathogens, as well as the implications for phagocytosis, autophagy, and polarization from proinflammatory to prohealing phenotype. We further discuss how this knowledge can be harnessed in regenerative medicine and for the design of new drugs and immune-modulatory drug delivery systems, biomaterials, and tissue scaffolds.

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