scholarly journals Omentin-1 Modulates Macrophage Function via Integrin Receptors αvβ3 and αvβ5 and Reverses Plaque Vulnerability in Animal Models of Atherosclerosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Xuze Lin ◽  
Yan Sun ◽  
Shiwei Yang ◽  
Mengyue Yu ◽  
Liu Pan ◽  
...  
Keyword(s):  
Animal Models ◽  
Inflammatory Cytokines ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Integrin Subunit ◽  
Integrin Receptors ◽  
Macrophage Function ◽  
Underlying Mechanisms ◽  
Pro Inflammatory Cytokines

Backgrounds: Omentin-1 is a novel cytokine that is primarily released by the epicardial adipose tissue. Molecular structure analysis revealed that it contained a fibrinogen-like domain. Clinical studies have demonstrated that the expression of omentin-1 is tightly associated with the development of cardiovascular diseases, but the receptor by which omentin-1 modulates macrophage function has not been identified yet.Objective: This study sought to investigate the effect of omentin-1 on already-established atherosclerosis (AS) lesions in both ApoE−/− and Ldlr−/− mice and further, study its underlying mechanisms.Methods and Results: We investigated the effect of omentin-1 on the plaque phenotype by implanting a minipump in ApoE−/− and Ldlr−/− mice. In vivo studies showed that the infusion of omentin-1 increased the collagen content and mitigated the formation of the necrotic core in both animal models. Immunohistochemistry and immunofluorescence analysis revealed that omentin-1 suppressed inflammatory cytokines expression, macrophage infiltration, and apoptosis within the plaque. An immunoprecipitation experiment and confocal microscopy analysis confirmed the binding of omentin-1 to the integrin receptors αvβ3 and αvβ5. The cell studies demonstrated that omentin-1 suppressed the apoptosis and inflammatory cytokines expression induced by the oxidized low-density lipoprotein in the macrophage. In addition, omentin-1 promoted the phosphorylation of the integrin-relevant signaling pathway as well as the Akt and AMPK in the macrophage. The addition of the inhibitor of the integrin receptor or interfering with the expression of the integrin subunit αv (ITGAV) both significantly abrogated the bioeffects induced by omentin-1. A flow cytometry analysis indicated that the antibodies against αvβ3 and αvβ5 had a competitive effect on the omentin-1 binding to the cell membrane.Conclusions: The administration of adipokine omentin-1 can inhibit the necrotic cores formation and pro-inflammatory cytokines expression within the AS lesion. The mechanisms may include the suppression of apoptosis and pro-inflammatory cytokines expression in the macrophage by binding to the integrin receptors αvβ3 and αvβ5.

Guggulsterone, a farnesoid X receptor antagonist lowers plasma trimethylamine-N-oxide levels: An evidence from in vitro and in vivo studies

2018 ◽  
Vol 38 (3) ◽  
pp. 356-370 ◽  
Author(s):  
A Gautam ◽  
YN Paudel ◽  
SAZ Abidin ◽  
U Bhandari
Keyword(s):  
Hepatic Injury ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Farnesoid X Receptor ◽  
Lipoprotein Cholesterol ◽  
In Vivo Studies ◽  
Low Density Lipoprotein Cholesterol ◽  
Pro Inflammatory Cytokines

The current study investigated the role of guggulsterone (GS), a farnesoid X receptor antagonist, in the choline metabolism and its trimethylamine (TMA)/flavin monooxygenases/trimethylamine- N-oxide (TMAO) inhibiting potential in a series of in vitro and in vivo studies as determined by high-performance liquid chromatography (HPLC), mass spectroscopy (MS), and liquid chromatography (LC)-MS techniques. Atherosclerosis (AS) was successfully induced in a group of experimental animals fed with 2% choline diet for 6 weeks. Serum lipid profiles such as total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol were measured. Pro-inflammatory cytokines levels, markers for a hepatic injury, and oxidative stress markers were assessed. Interestingly, GS reduced the level of TMA/TMAO in both in vitro and in vivo studies as demonstrated by the peaks obtained from HPLC, MS, and LC–MS. Furthermore, GS exhibited cardioprotective and antihyperlipidemic effects as evidenced by the attenuation of levels of several serum lipid profiles and different atherogenic risk predictor indexes. GS also prevented hepatic injury by successfully restoring the levels of hepatic injury biomarkers to normal. Similarly, GS inhibited the production of pro-inflammatory cytokines levels, as well as GS, enhanced antioxidant capacity, and reduced lipid peroxidation. Histopathological study of aortic sections demonstrated that GS maintained the normal architecture in AS-induced rats. On the basis of results obtained from current investigation, we suggest that GS might have a great therapeutic potential for the treatment of AS.

PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1

2019 ◽  
Vol 116 (5) ◽  
pp. 908-915 ◽  
Author(s):  
Zufeng Ding ◽  
Naga Venkata K Pothineni ◽  
Akshay Goel ◽  
Thomas F Lüscher ◽  
Jawahar L Mehta
Keyword(s):  
Inflammatory Cytokines ◽  
Ldl Cholesterol ◽  
Vascular Endothelial Cells ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Pcsk9 Inhibitors ◽  
Prevention Of Atherosclerosis ◽  
Pro Inflammatory Cytokines

Abstract PCSK9 degrades low-density lipoprotein cholesterol (LDL) receptors and subsequently increases serum LDL cholesterol. Clinical trials show that inhibition of PCSK9 efficiently lowers LDL cholesterol levels and reduces cardiovascular events. PCSK9 inhibitors also reduce the extent of atherosclerosis. Recent studies show that PCSK9 is secreted by vascular endothelial cells, smooth muscle cells, and macrophages. PCSK9 induces secretion of pro-inflammatory cytokines in macrophages, liver cells, and in a variety of tissues. PCSK9 regulates toll-like receptor 4 expression and NF-κB activation as well as development of apoptosis and autophagy. PCSK9 also interacts with oxidized-LDL receptor-1 (LOX-1) in a mutually facilitative fashion. These observations suggest that PCSK9 is inter-twined with inflammation with implications in atherosclerosis and its major consequence—myocardial ischaemia. This relationship provides a basis for the use of PCSK9 inhibitors in prevention of atherosclerosis and related clinical events.

scholarly journals IL-17-differentiated macrophages secrete pro-inflammatory cytokines in response to oxidized low-density lipoprotein

2017 ◽  
Vol 16 (1) ◽  
Author(s):  
María de la Paz Sánchez-Martínez ◽  
Francisco Blanco-Favela ◽  
Mónica Daniela Mora-Ruiz ◽  
Adriana Karina Chávez-Rueda ◽  
Mariela Bernabe-García ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Pro Inflammatory Cytokines

scholarly journals ATP-release drives inflammation with lysophosphatidylcholine

2020 ◽  
Author(s):  
Sana Ismaeel ◽  
Ayub Qadri
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Purinergic Signaling ◽  
Low Density Lipoprotein ◽  
Neuronal Cells ◽  
Atp Release ◽  
Density Lipoprotein ◽  
Independent Manner ◽  
Caspase 1

AbstractLysophosphatidylcholine (LPC), a dominant lipid component of oxidized low-density lipoprotein, plays a major role in inflammation associated with atherosclerosis and neurodegenerative disorders. It activates inflammatory responses from macrophages, neuronal cells and endothelial cells. However, the exact mechanism by which LPC promotes inflammation remains incompletely understood. Here, we show that the production of inflammatory cytokines and cytotoxicity with LPC are both critically dependent on its ability to bring about release of ATP from cells. The induction of caspase-1-mediated IL-1β-release with LPC from TLR-primed macrophages and neuronal cells is reduced in presence of ATP-hydrolyzing enzyme, apyrase and the inhibitors of purinergic signaling. ATP released from LPC-treated cells also promotes an IL-12p70hi, low phagocytic and poorly co-stimulatory phenotype in macrophages in a caspase-1 – independent manner. Treatment with apyrase reduces production of inflammatory cytokines with LPC in vivo. These findings reveal a previously unappreciated pathway for generation of inflammatory responses with LPC, and these have significant implications for therapeutic intervention in chronic inflammatory disorders promoted by this lipid.

scholarly journals PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36

Circulation ◽  
2021 ◽  
Vol 143 (1) ◽  
pp. 45-61 ◽  
Author(s):  
Zhiyong Qi ◽  
Liang Hu ◽  
Jianjun Zhang ◽  
Wenlong Yang ◽  
Xin Liu ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Low Density Lipoprotein ◽  
Atp Release ◽  
Density Lipoprotein ◽  
Dense Granule ◽  
Clot Retraction ◽  
Pcsk9 Inhibitors ◽  
Infarct Expansion ◽  
Underlying Mechanisms

Background: PCSK9 (proprotein convertase subtilisin/kexin 9), mainly secreted by the liver and released into the blood, elevates plasma low-density lipoprotein cholesterol by degrading low-density lipoprotein receptor. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, and the underlying mechanisms, as well, still remain unclear. Methods: We detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, α-granule release, spreading, and clot retraction. These studies were complemented by in vivo analysis of FeCl 3 -injured mouse mesenteric arteriole thrombosis. We also investigated the underlying mechanisms. Using the myocardial infarction (MI) model, we explored the effects of PCSK9 on microvascular obstruction and infarct expansion post-MI. Results: PCSK9 directly enhances agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, P-selectin release from α-granules, spreading, and clot retraction. In line, PCSK9 enhances in vivo thrombosis in a FeCl 3 -injured mesenteric arteriole thrombosis mouse model, whereas PCSK9 inhibitor evolocumab ameliorates its enhancing effects. Mechanism studies revealed that PCSK9 binds to platelet CD36 and thus activates Src kinase and MAPK (mitogen-activated protein kinase)–extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase, increases the generation of reactive oxygen species, and activates the p38MAPK/cytosolic phospholipase A2/cyclooxygenase-1/thromboxane A 2 signaling pathways downstream of CD36 to enhance platelet activation, as well. Using CD36 knockout mice, we showed that the enhancing effects of PCSK9 on platelet activation are CD36 dependent. It is important to note that aspirin consistently abolishes the enhancing effects of PCSK9 on platelet activation and in vivo thrombosis. Last, we showed that PCSK9 activating platelet CD36 aggravates microvascular obstruction and promotes MI expansion post-MI. Conclusions: PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, and MI expansion post-MI, as well, by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors or aspirin abolish the enhancing effects of PCSK9, supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.

Abstract 457: Transcription Coactivator MED1 Protects Against Atherosclerosis by Modulation of Macrophage Polarization

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Liang Bai ◽  
Enqi Liu
Keyword(s):  
Gene Expression ◽  
Macrophage Polarization ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Peritoneal Macrophages ◽  
Gene Markers ◽  
Underlying Mechanisms ◽  
High Level

Mediator 1 (MED1), a key subunit of the Mediator complex, interacts with several nuclear receptors and transcription factors to direct gene-specific transcription. It is well-known that MED1 play important roles in lipid metabolism. However, the role and underlying mechanisms of MED1 in atherosclerosis remains unclear. Here, macrophage-specific MED1 knockout (MED1 ΔMac ) mice were generated to investigate the contribution of MED1 on atherogenesis in vivo. We demonstrate that among mice deficient in apolipoprotein E (Apoe), the additional loss of macrophage MED1 (MED1 ΔMac /ApoE -/- ) exhibited significantly larger atherosclerotic lesions in the whole aortic tree and aortic root compared with MED1 fl/fl /ApoE -/- littermates on either the chow or the western diet, and these effects were also found in low-density lipoprotein (LDL) receptor-deficient (LDLR -/- ) mice reconstituted with bone marrow from MED1 ΔMac mice. Peritoneal macrophages from MED1 ΔMac /ApoE -/- mice had significantly increased expression of gene markers for M1-like macrophages, including IL-1β, IL6,COX2, iNOS, Gro1, MCP1 and TNFα, etc, whereas decreased levels of anti-inflammatory genes for M2-like macrophages, such as Arg1, Mrc1, Retnla, Chi3l3 and PPARγ. Over-expression of MED1 using adenovirally-driven MED1 (Ad/MED1) in MED1 fl/fl /ApoE -/- macophages repressed the proinflammatory gene expression. Re-expression of MED1 using Ad/MED1 counteracted the high level of inflammatory gene in MED1 ΔMac /ApoE -/- macophages. Furthermore, gene expression profiling and PCR array showed that MED1-deficient macrophages exhibited the increased M1 targets and decreased M2 targets. These data demonstrate that MED1 expression by macrophages has anti-atherogenic effects via regulation of macrophage polarization. MED1 may be considered as a potential therapeutic target to treat atherosclerosis.

The effect of antidepressants on inflammatory markers in animal models of depression

2011 ◽  
Vol 26 (S2) ◽  
pp. 2091-2091
Author(s):  
A. Harkin ◽  
T.J. Connor
Keyword(s):  
Animal Models ◽  
Inflammatory Cytokines ◽  
Glial Cells ◽  
Inflammatory Cytokine ◽  
Animal Models Of Depression ◽  
In Vitro Exposure ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Considering the evidence that pro-inflammatory cytokines play a causal role in depressive illness, the ability of antidepressants to induce anti-inflammatory effects is a subject of considerable interest. In an in vivo context we observe that antidepressants that enhance noradrenaline availability are the most effective anti-inflammatory agents; a fact consistent with the established anti-inflammatory actions of noradrenaline. Specifically, we have observed that noradrenaline reuptake inhibitors (NRIs) inhibit microglial activation and inhibit expression of pro-inflammatory cytokines (IL-1beta and TNF-alpha), iNOS, and inflammatory chemokines (IP-10 and RANTES) in rat brain following a systemic inflammatory challenge. These in vivo anti-inflammatory actions of NRIs are mimicked by in vitro exposure of primary glial cells to noradrenaline, but not by in vitro exposure of glial cells to the drugs themselves. These data suggest that NRIs promote an anti-inflammatory environment in rat brain in vivo by increasing noradrenaline availability at glial cells. We have also observed that even in the absence of any overt inflammation, chronic treatment with the NRI reboxetine promotes an anti-inflammatory phenotype in the CNS characterised by reduced expression of pro-inflammatory cytokine IFN-gamma, and increased expression of the anti-inflammatory cytokine IL-10. Current experiments are focused on the activation of the inflammatory response system in animal models of depression secondary to inflammation. The models are used subsequently to assess the anti-inflammatory effects of antidepressants in vivo.

Abstract 583: RNAi Therapeutics For The Lowering Of Cholesterol

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kevin Fitzgerald ◽  
Maria Frank-Kamenetsky ◽  
Tracy S Zimmermann ◽  
Jay Horton ◽  
Akin Akinc ◽  
...  
Keyword(s):  
Animal Models ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Small Interfering Rnas ◽  
Systemic Delivery ◽  
Apob Mrna ◽  
New Class ◽  
Safety Studies ◽  
Rnai Therapeutics

Delivery of small interfering RNAs (siRNAs) in vivo , using clinically relevant modes of administration, is critical for the advancement of RNA interference (RNAi) therapeutics. In this work, we demonstrate systemic delivery of siRNAs and potent in vivo down-modulation of two important disease targets, apolipoprotein B (apoB) and proprotein convertase subtilisin kexin 9 (PCSK9). A single injection of liposomal siRNA resulted in >90% silencing of apoB mRNA expression in the liver 48 h after administration. The effect was demonstrated to occur through cleavage of the apoB mRNA at precisely the site predicted for the RNAi mechanism. Reductions in apoB protein, cholesterol, and low-density lipoprotein (LDLc) levels were observed in 48 hours that lasted for at least 23 days, thus demonstrating an immediate, potent and durable biological effect. In addition to apoB we have also demonstrated the ability to down-modulate other important liver targets such as PCSK9. PCSK9 has been closely implicated in LDLc regulation. We have demonstrated PCSK9 down-modulation in several animal models including, mouse, humanized mouse, rat, and non-human primate. Down-modulation of PCSK9 levels resulted in significant lowering of cholesterol (20 – 60%) in all animal models tested. These findings strongly support the potential of RNAi therapeutics as a new class of drug for metabolic and cardiovascular diseases. Our next steps include selecting the most potent lead molecule and moving it into GLP safety studies.

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