Silencing of junctional adhesion molecule-like protein attenuates atherogenesis and enhances plaque stability in ApoE−/− mice

2019 ◽  
Vol 133 (11) ◽  
pp. 1215-1228 ◽  
Author(s):  
Yu Sun ◽  
Juan Guan ◽  
Yunfeng Hou ◽  
Fei Xue ◽  
Wei Huang ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Wound Repair ◽  
Inflammatory Responses ◽  
Atherosclerotic Lesion ◽  
Atherosclerotic Plaques ◽  
Plaque Stability ◽  
Fibrous Cap ◽  
Enhanced Expression

Abstract Background: Although junctional adhesion molecule-like protein (JAML) has recently been implicated in leukocyte recruitment during inflammation and wound repair, its role in atherosclerosis remains to be elucidated. Methods and results: First, we showed that JAML was strongly expressed in atherosclerotic plaques of cardiovascular patients. Similar results were obtained with atherosclerotic plaques of ApoE−/− mice. Co-immunofluorescence staining showed that JAML was mainly expressed in macrophages. Enhanced expression of JAML in cultured macrophages was observed following exposure of the cells to oxLDL. The functional role of JAML in atherosclerosis and macrophages function was assessed by interference of JAML with shRNA in vivo and siRNA in vitro. Silencing of JAML in mice significantly attenuated atherosclerotic lesion formation, reduced necrotic core area, increased plaque fibrous cap thickness, decreased macrophages content and inflammation. In addition, histological staining showed that JAML deficiency promoted plaques to stable phenotype. In vitro, JAML siRNA treatment lowered the expression of inflammatory cytokines in macrophages treated with oxLDL. The mechanism by which JAML mediated the inflammatory responses may be related to the ERK/NF-κB activation. Conclusions: Our results demonstrated that therapeutic drugs which antagonize the function of JAML may be a potentially effective approach to attenuate atherogenesis and enhance plaque stability.

scholarly journals Reactive oxygen species scavenging and inflammation mitigation enabled by biomimetic prussian blue analogues boycott atherosclerosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yan Zhang ◽  
Yifei Yin ◽  
Wei Zhang ◽  
Hongyan Li ◽  
Taixia Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Prussian Blue ◽  
Foam Cell ◽  
Atherosclerotic Plaques ◽  
Fibrous Cap ◽  
Theranostic Agent ◽  
Fibrous Cap Thickness ◽  
Anti Inflammation

Abstract Background As one typical cardiovascular disease, atherosclerosis severely endanger people’ life and cause burden to people health and mentality. It has been extensively accepted that oxidative stress and inflammation closely correlate with the evolution of atherosclerotic plaques, and they directly participate in all stages of atherosclerosis. Regarding this, anti-oxidation or anti-inflammation drugs were developed to enable anti-oxidative therapy and anti-inflammation therapy against atherosclerosis. However, current drugs failed to meet clinical demands. Methods Nanomedicine and nanotechnology hold great potential in addressing the issue. In this report, we engineered a simvastatin (Sim)-loaded theranostic agent based on porous manganese-substituted prussian blue (PMPB) analogues. The biomimetic PMPB carrier could scavenge ROS and mitigate inflammation in vitro and in vivo. Especially after combining with Sim, the composite Sim@PMPB NC was expected to regulate the processes of atherosclerosis. As well, Mn2+ release from PMPB was expected to enhance MRI. Results The composite Sim@PMPB NC performed the best in regulating the hallmarks of atherosclerosis with above twofold decreases, typically such as oxidative stress, macrophage infiltration, plaque density, LDL internalization, fibrous cap thickness and foam cell birth, etc. Moreover, H2O2-induced Mn2+ release from PMPB NC in atherosclerotic inflammation could enhance MRI for visualizing plaques. Moreover, Sim@PMPB exhibited high biocompatibility according to references and experimental results. Conclusions The biomimetic Sim@PMPB theranostic agent successfully stabilized atherosclerotic plaques and alleviated atherosclerosis, and also localized and magnified atherosclerosis, which enabled the monitoring of H2O2-associated atherosclerosis evolution after treatment. As well, Sim@PMPB was biocompatible, thus holding great potential in clinical translation for treating atherosclerosis. Graphic abstract

scholarly journals Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability

2018 ◽  
Vol 45 (3) ◽  
pp. 1034-1050 ◽  
Author(s):  
Jing Liu ◽  
Jibin Lin ◽  
Shaolin He ◽  
Chun Wu ◽  
Boyuan Wang ◽  
...  
Keyword(s):  
Immunohistochemical Staining ◽  
Intracellular Cytokine Staining ◽  
Flow Cytometric Analysis ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
Atherosclerotic Plaques ◽  
Plaque Stability ◽  
Atherosclerotic Burden

Background/Aims: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. Methods: IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting. Results: Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4+ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. Conclusion: IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease.

Abstract 5788: VCAM-1 Targeted PET-CT Detects Inflammatory Atherosclerotic Plaques

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Matthias Nahrendorf ◽  
Edmund Keliher ◽  
Peter Panizzi ◽  
Hanwen Zhang ◽  
Sheena Hembrador ◽  
...  
Keyword(s):  
Dynamic Range ◽  
Atherosclerotic Lesion ◽  
Vascular Anatomy ◽  
High Sensitivity ◽  
Ct Imaging ◽  
Atherosclerotic Plaques ◽  
Mrna Levels ◽  
Pet Ct

Hybrid PET-CT imaging of VCAM-1 expression and vascular anatomy may facilitate simultaneous assessment of atherosclerotic lesion biology and morphology, and enhance risk assessment in individual patients. We used combined in vitro/in vivo screening of candidate affinity ligands and developed a PET reporter for imaging VCAM-1 expression with high sensitivity, specificity and translational potential. Three different phage display-derived VCAM-1 affinity peptides were tested using immobilized VCAM-1, VCAM-1 expressing cells and apoE−/− mice. A compound with a linear peptide and arborising tetrameric design showed high affinity (86.6 nM) and specificity for VCAM-1 (97% inhibition with soluble VCAM-1). This lead compound was derivatized with 18Fluorine to synthesize the clinically viable PET agent 18F-4V. In vivo PET-CT imaging showed robust uptake of 18F-4V in plaque laden arterial sections from 8 apoE−/− mice, significantly higher than in 4 wild type mice and attenuated by atorvastatin treatment (p<0.05). 18F-4V uptake was confirmed in excised aortas, colocalized with atherosclerotic plaques delineated by Oil Red O staining and correlated with mRNA levels of VCAM-1 measured by quantitative RT-PCR (R2=0.62, p=0.03). 18F-4V allows noninvasive PET-CT imaging of VCAM-1 in atheromata, has sufficient dynamic range to quantify treatment effects, and correlates with inflammatory gene expression. This approach lends itself to seamless translation to human PET-CT imaging.

Abstract 446: EphA2 Regulates Vascular Smooth Muscle Fibroproliferative Remodeling in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Alexandra C Finney ◽  
Jonette M Green ◽  
Mohammad A Rana ◽  
Steven D Funk ◽  
James G Traylor ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Knockout Mice ◽  
Tyrosine Kinases ◽  
Atherosclerotic Plaques ◽  
Eph Receptors ◽  
Matrix Deposition ◽  
Enhanced Expression

Eph receptors, the largest mammalian subfamily of receptor tyrosine kinases, regulate inflammation and tissue remodeling. The EphA2 receptor shows enhanced expression in atherosclerosis, and deletion of EphA2 in atherosclerosis-prone ApoE knockout mice attenuates lesion formation. We now show that EphA2 knockout mice exhibit reduced late stage plaque progression associated with diminished smooth muscle content. While EphA2 is absent in quiescent vascular smooth muscle cells in vitro and in vivo , dedifferentiation to a synthetic phenotype significantly upregulates EphA2 expression. Deletion of EphA2, a known oncogene, reduces markers of proliferation in atherosclerotic plaques, and EphA2 knockdown similarly reduces vascular smooth muscle proliferation in culture with associated reductions in serum-induced ERK and Akt signaling. In addition to proliferation, EphA2 knockout mice show significantly reduced collagen content in their atherosclerotic plaques, and EphA2 knockdown reduces smooth muscle matrix deposition in vitro . Together these data suggest a potential role for EphA2 in smooth-muscle driven vascular fibroproliferative remodeling, representing the first link between EphA2 signaling and smooth muscle function.

Abstract 1131: PARP1 is required for Adhesion Molecule Expression in Atherogenesis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Tobias Lukowicz von ◽  
Paul O Hassa ◽  
Christine Lohmann ◽  
Jan Borén ◽  
Vincent Braunersreuther ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Endothelial Activation ◽  
Chronic Inflammatory Disease ◽  
Parp Inhibition ◽  
High Cholesterol Diet ◽  
Fibrous Cap ◽  
Parp Activity

Objective - Atherosclerosis is a chronic inflammatory disease resulting from the interaction between modified lipoproteins, activated endothelial cells, macrophages, T-cells, and elements of the arterial wall. However, the key mediators linking recruitment of inflammatory cells to atherogenesis remain poorly defined. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme that plays a role in acute inflammatory responses of cells and organs. Methods and Results - After 12 weeks of high-cholesterol diet, plaque formation in male apolipoprotein E- deficient mice was decreased by chronic inhibition of enzymatic PARP activity or genetic deletion of PARP1 by 46 or 51 %, respectively ( P < 0.05, n ≥ 9). Pharmacological PARP inhibition using PJ34 or PARP 1 deletion reduced PARP activity and diminished expression of inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), P-, and E-selectin (see Figure ). Furthermore, chronic PARP inhibition reduced plaque macrophage (CD68) and T-cell infiltration (CD3), increased fibrous cap thickness, and decreased necrotic core size and cell death ( P < 0.05, n ≥ 6). Conclusions - Our data provide pharmacologic and genetic evidence that endogenous PARP1 is required for the development of atherosclerosis in vivo by increasing adhesion molecules due to endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability. Thus, inhibition of PARP1 may represent a promising novel therapeutic target in atherosclerosis.

scholarly journals Reduced atherosclerosis lesion size, inflammatory response in miR-150 knockout mice via macrophage effects

2018 ◽  
Vol 59 (4) ◽  
pp. 658-669 ◽  
Author(s):  
Fu-Han Gong ◽  
Wen-Lin Cheng ◽  
Haiping Wang ◽  
Maomao Gao ◽  
Juan-Juan Qin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Knockout Mice ◽  
Noncoding Rna ◽  
Inflammatory Responses ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Endothelial Cell Proliferation ◽  
Double Knockout

Atherosclerosis is considered to be a chronic inflammatory disease that can lead to severe clinically important cardiovascular events. miR-150 is a small noncoding RNA that significantly enhances inflammatory responses by upregulating endothelial cell proliferation and migration, as well as intravascular environmental homeostasis. However, the exact role of miR-150 in atherosclerosis remains unknown. Here, we investigated the effect of miR-150 deficiency on atherosclerosis development. Using double-knockout (miR-150−/− and ApoE−/−) mice, we measured atherosclerotic lesion size and stability. Meanwhile, we conducted in vivo bone marrow transplantation to identify cellular-level components of the inflammatory response. Compared with mice deficient only in ApoE, the double-knockout mice had significantly smaller atherosclerotic lesions and displayed an attenuated inflammatory response. Moreover, miR-150 ablation promoted plaque stabilization via increases in smooth muscle cell and collagen content and decreased macrophage infiltration and lipid accumulation. The in vitro experiments indicated that an inflammatory response with miR-150 deficiency in atherosclerosis results directly from upregulated expression of the cytoskeletal protein, PDZ and LIM domain 1 (PDLIM1), in macrophages. More importantly, the decreases in phosphorylated p65 expression and inflammatory cytokine secretion induced by miR-150 ablation were reversed by PDLIM1 knockdown. These findings suggest that miR-150 is a promising target for the management of atherosclerosis.

scholarly journals Carbon Monoxide-Releasing Molecule-2 Ameliorates Particulate Matter-Induced Aorta Inflammation via Toll-Like Receptor/NADPH Oxidase/ROS/NF-κB/IL-6 Inhibition

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Thi Thuy Tien Vo ◽  
Chien-Yi Hsu ◽  
Yinshen Wee ◽  
Yuh-Lien Chen ◽  
Hsin-Chung Cheng ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Particulate Matter ◽  
Nadph Oxidase ◽  
Adhesion Molecule ◽  
Inflammatory Responses ◽  
Air Pollutant ◽  
Matrix Metalloproteinase 2 ◽  
Beneficial Effects

Particulate matter (PM), a major air pollutant, may be associated with adverse cardiovascular effects. Reactive oxygen species- (ROS-) dependent proinflammatory cytokine production, such as interleukin-6 (IL-6), is a possible underlying mechanism. Carbon monoxide- (CO-) releasing molecule-2 (CORM-2) which liberates exogenous CO can exert many beneficial effects, particularly anti-inflammation and antioxidant effects. The purpose of this study was to explore the protective effects and underpinning mechanisms of CORM-2 on PM-induced aorta inflammation. Here, human aortic vascular smooth muscle cells (HASMCs) were utilized as in vitro models for the assessment of signaling pathways behind CORM-2 activities against PM-induced inflammatory responses, including Toll-like receptors (TLRs), NADPH oxidase, ROS, nuclear factor-kappa B (NF-κB), and IL-6. The modulation of monocyte adherence and HASMC migration, that are two critical cellular events of inflammatory process, along with their regulators, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and matrix metalloproteinase-2 (MMP-2) and MMP-9, in response to PM by CORM-2, were further evaluated. Finally, mice experiments under different conditions were conducted for the in vivo evaluation of CORM-2 benefits on the expression of inflammatory molecules including IL-6, ICAM-1, VCAM-1, MMP-2, and MMP-9. Our results found that PM could induce aorta inflammation in vitro and in vivo, as evidenced by the increase of IL-6 expression that was regulated by the TLR2 and TLR4/NADPH oxidase/ROS/NF-κB signaling pathway, thereby promoting ICAM-1- and VCAM-1-dependent monocyte adhesion and MMP-2- and MMP-9-dependent HASMC migration. Importantly, our experimental models demonstrated that CORM-2-liberated CO effectively inhibited the whole identified PM-induced inflammatory cascade in HASMCs and tissues. In conclusion, CORM-2 treatment may elicit multiple beneficial effects on inflammatory responses of aorta due to PM exposure, thereby providing therapeutic value in the context of inflammatory diseases of the cardiovascular system.

IgG1 phosphorylcholine ameliorates plaque stability via reduced intraplaque angiogenesis and intraplaque haemorrhage in a murine atherosclerosis model

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M De Vries ◽  
F Baganha ◽  
R.C.M De Jong ◽  
H.A.B Peters ◽  
K Petterson ◽  
...  
Keyword(s):  
Vein Graft ◽  
Medical Center ◽  
Animal Experiments ◽  
Atherosclerotic Lesion ◽  
Inflammatory Cells ◽  
Intraplaque Hemorrhage ◽  
Funding Source ◽  
Plaque Stability

Abstract Background Phosphorylcholine, (PC) the polar headgroup of the dominating membrane phospholipid phosphatidylcholine, is one of the main oxLDL epitopes and an important pro-inflammatory damage associated molecular pattern. Experimental and epidemiologic data show that natural anti-PC IgM protect against cardiovascular disease. Within atherosclerotic lesions, inflammatory and angiogenesis processes are interdependent and contribute to plaque destabilization. Atherosclerotic lesion resident CD163+ macrophages promote leukocyte infiltration but also induce angiogenesis and vessel permeability by secreting VEGFA. PC antibodies are recognized for their anti-inflammatory properties. However, the effect of PC antibodies on intraplaque angiogenesis (IPA) and intraplaque hemorrhage (IPH), the main entrance route for inflammatory cells in advanced lesions, is unknown. Purpose To investigate the therapeutic effect of a new IgG1 PC antibody (PCmAB) on lesion development, IPA and IPH in murine vein graft atherosclerosis. Methods All animal experiments were performed in compliance with Dutch government guidelines and the Directive 2010/63/EU of the European Parliament. Hypercholesterolemic male ApoE3*Leiden mice received a (donor) caval vein interposition in the carotid artery. Mice received weekly ip injections of (5mg/kg) PCmAb (n=11) or vehicle (n=12) until sacrifice at day 28. Immunohistochemistry was used to evaluate vein graft morphometry and lesion composition including IPA and IPH. PCmAB isolated effects on pro-angiogenic and pro-inflammatory behaviour was investigated in vitro in HUVECs and Hemoglobin (Hb):Haptoglobin (Hp)-cultured THP-1 macrophages. Results PCmAB treatment decreased vein graft media area (13%) and intima lesion (25%), but more importantly increased lumen area with 53% when compared to vehicle treatment. PCmAb improved lesion stability by increasing collagen content (18%) and by decreasing macrophages presence (31%). VCAM-1 and ICAM-1 expression in the vessel wall were also reduced (resp.29% and 36%) by PCmAb. PCmAb improved IPA by a significant reduction in neovessel density of 34%. This was supported in vitro by significant reduced EC proliferation and migration upon PCmAB with and without oxLDL stimulation. Moreover, PCmAb enhanced maturation of intraplaque angiogenic vessels by increasing neovessel pericyte coverage in vivo (31%). Together, this resulted in a reduction of IPH of 62% in the PCmAB group. PCmAb resulted in decreased macrophages CD163+ content in vein grafts by 23% whereas CD163 expression was reduced by PCmAb in Hb:Hp stimulated macrophages. Conclusion PCmAB is an effective inhibitor of atherosclerotic lesion formation in ApoE3*Leiden mice. PCmAb reduces IPA and IPH by decreased neovessel density and (CD163+) macrophages influx via reduced expression of VCAM-1 and ICAM-1, and increased neovessel maturation in vein graft atherosclerosis. PCmAB holds a promise as a new therapeutic approach for plaque stability. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Leiden University Medical Center

scholarly journals Epithelial CD47 is critical for mucosal repair in the murine intestine in vivo

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Michelle Reed ◽  
Anny-Claude Luissint ◽  
Veronica Azcutia ◽  
Shuling Fan ◽  
Monique N. O’Leary ◽  
...  
Keyword(s):  
Wound Healing ◽  
Epithelial Cell ◽  
Wound Repair ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Primary Cultures ◽  
Intestinal Barrier ◽  
Mucosal Repair

Abstract CD47 is a ubiquitously expressed transmembrane glycoprotein that regulates inflammatory responses and tissue repair. Here, we show that normal mice treated with anti-CD47 antibodies, and Cd47-null mice have impaired intestinal mucosal wound healing. Furthermore, intestinal epithelial cell (IEC)-specific loss of CD47 does not induce spontaneous immune-mediated intestinal barrier disruption but results in defective mucosal repair after biopsy-induced colonic wounding or Dextran Sulfate Sodium (DSS)-induced mucosal damage. In vitro analyses using primary cultures of CD47-deficient murine colonic IEC or human colonoid-derived IEC treated with CD47-blocking antibodies demonstrate impaired epithelial cell migration in wound healing assays. Defective wound repair after CD47 loss is linked to decreased epithelial β1 integrin and focal adhesion signaling, as well as reduced thrombospondin-1 and TGF-β1. These results demonstrate a critical role for IEC-expressed CD47 in regulating mucosal repair and raise important considerations for possible alterations in wound healing secondary to therapeutic targeting of CD47.

scholarly journals Weak UVB Irradiation Promotes Macrophage M2 Polarization and Stabilizes Atherosclerosis

2021 ◽  
Author(s):  
Xin-Yun Li ◽  
Tao Qin ◽  
Peng-Fei Zhang ◽  
Wen-jiang Yan ◽  
Ling-Li Lei ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Macrophage Polarization ◽  
Atherosclerotic Lesion ◽  
Ultraviolet B ◽  
M2 Macrophage ◽  
Uvb Irradiation ◽  
Plaque Stability ◽  
M1 Macrophage

AbstractAtherosclerosis (AS) is a chronic cardiovascular disease endangering human health and is one of the most common causes of myocardial infarction and stroke. Macrophage polarization plays a vital role in regulating plaque stability. As an important component of sunlight, ultraviolet B (UVB) has been proven to promote vitamin D and nitric oxide synthesis. This research used an AS model in ApoE−/− mice to study the effects of UVB on macrophage polarization and atherosclerotic plaque stability. In vitro, UVB irradiation increased arginase-I (Arg-I, M2 macrophage) and macrophage mannose receptor (CD206) expression, while the expression of inducible nitric oxide synthase (iNOS) (M1 macrophage) and CD86 was decreased. UVB promoted Akt phosphorylation in vitro. In vivo, UVB irradiation promoted the stabilization of atherosclerotic lesion plaques, while the phenotype of M2 macrophages increased. Our research provides new evidence for UVB in preventing and treating atherosclerosis.

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