Myeloid Ezh2 Deficiency Limits Atherosclerosis Development

Macrophages define a key component of immune cells present in atherosclerotic lesions and are central regulators of the disease. Since epigenetic processes are important in controlling macrophage function, interfering with epigenetic pathways in macrophages might be a novel approach to combat atherosclerosis. Histone H3K27 trimethylation is a repressive histone mark catalyzed by polycomb repressive complex with EZH2 as the catalytic subunit. EZH2 is described to increase macrophage inflammatory responses by supressing the suppressor of cytokine signaling, Socs3. We previously showed that myeloid deletion of Kdm6b, an enzymes that in contrast to EZH2 removes repressive histone H3K27me3 marks, results in advanced atherosclerosis. Because of its opposing function and importance of EZH2 in macrophage inflammatory responses, we here studied the role of myeloid EZH2 in atherosclerosis. A myeloid-specific Ezh2 deficient mouse strain (Ezh2del) was generated (LysM-cre+ x Ezh2fl/fl) and bone marrow from Ezh2del or Ezh2wt mice was transplanted to Ldlr-/- mice which were fed a high fat diet for 9 weeks to study atherosclerosis. Atherosclerotic lesion size was significantly decreased in Ezh2del transplanted mice compared to control. The percentage of macrophages in the atherosclerotic lesion was similar, however neutrophil numbers were lower in Ezh2del transplanted mice. Correspondingly, the migratory capacity of neutrophils was decreased in Ezh2del mice. Moreover, peritoneal Ezh2del foam cells showed a reduction in the inflammatory response with reduced production of nitric oxide, IL-6 and IL-12. In Conclusion, myeloid Ezh2 deficiency impairs neutrophil migration and reduces macrophage foam cell inflammatory responses, both contributing to reduced atherosclerosis.

Download Full-text

Abstract 644: CD36 is Essential to Increased Atherosclerosis Mediated by Oral Infection With Porphromonas gingivalis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.644 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Maria Febbraio ◽

Paul M Brown

Keyword(s):

Periodontal Disease ◽

Inflammatory Responses ◽

Foam Cell ◽

Cell Formation ◽

Atherosclerotic Lesion ◽

Lipid Lowering ◽

Foam Cell Formation ◽

Dependent Manner ◽

Tlr2 Expression ◽

Macrophage Foam Cell

Epidemiological evidence strongly support a link between periodontal disease & cardiovascular disease, but the mechanism(s) remains poorly understood. Using the human periodontal disease associated bacteria, Porphyromonas gingivalis (Pg) as a model, we carried out studies in macrophages & low density lipoprotein receptor (LDLR) KO mice. Pg associated similarly with macrophages from wild type & CD36 KO mice, but there were differences in responses dependent on Toll-like receptor (TLR) 2. We observed decreased NFkB activation & IL1beta generation following Pg treatment in CD36 KO macrophages, despite similar levels of TLR2 expression. OxLDL strongly inhibited Pg mediated IL-1beta generation in a CD36 dependent manner. Macrophage foam cell formation as a result of incubation with oxLDL & PgLPS was increased in a CD36 dependent manner. LDLR KO & CD36/LDLR double KO mice were orally infected with Pg & fed a Western diet (12 weeks). There was a significant increase in the cemento-enamel junction of molars of infected compared with uninfected mice, demonstrating the validity of the model. Histological analysis showed inflammatory cell infiltrates in gums of infected mice after 12 weeks, supporting a chronic inflammatory process. Differences in plasma parameters & weight gain did not necessarily track with atherosclerosis burden, however blood neutrophils & cytokines were increased in infected LDLR KO mice compared with all other groups. Infected LDLR KO mice had significantly increased atherosclerotic lesion burden compared with uninfected LDLR KO mice, and all of the increased lesion was CD36-dependent. Our data suggest that atherosclerosis associated with periodontal disease is mediated by cellular inflammatory responses involving both CD36 & TLR2. Pg enhances oxLDL mediated foam cell formation in a CD36 dependent manner, and this may explain increased lesion burden. Generation of IL1beta, a key pro-atherogenic cytokine, is altered as a result of CD36 expression. Periodontal disease affects more than 20% of the population of the US/Canada, & is associated with increasing age, which is also a risk factor for atherosclerosis. Targeting CD36 may provide important supplemental therapy to current lipid lowering strategies to reduce atherosclerosis.

Download Full-text

Inhibitory effects of vasostatin-1 against atherogenesis

Clinical Science ◽

10.1042/cs20180451 ◽

2018 ◽

Vol 132 (23) ◽

pp. 2493-2507 ◽

Cited By ~ 2

Author(s):

Yuki Sato ◽

Rena Watanabe ◽

Nozomi Uchiyama ◽

Nana Ozawa ◽

Yui Takahashi ◽

...

Keyword(s):

Adhesion Molecule ◽

Inflammatory Responses ◽

Foam Cell ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

Inhibitory Effects ◽

Macrophage Foam Cell ◽

Down Regulation ◽

Atherosclerotic Lesions

Vasostatin-1, a chromogranin A (CgA)-derived peptide (76 amino acids), is known to suppress vasoconstriction and angiogenesis. A recent study has shown that vasostatin-1 suppresses the adhesion of human U937 monocytes to human endothelial cells (HECs) via adhesion molecule down-regulation. The present study evaluated the expression of vasostatin-1 in human atherosclerotic lesions and its effects on inflammatory responses in HECs and human THP-1 monocyte-derived macrophages, macrophage foam cell formation, migration and proliferation of human aortic smooth muscle cells (HASMCs) and extracellular matrix (ECM) production by HASMCs, and atherogenesis in apolipoprotein E-deficient (ApoE−/−) mice. Vasostatin-1 was expressed around Monckeberg’s medial calcific sclerosis in human radial arteries. Vasostatin-1 suppressed lipopolysaccharide (LPS)-induced up-regulation of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HECs. Vasostatin-1 suppressed inflammatory M1 phenotype and LPS-induced interleukin-6 (IL-6) secretion via nuclear factor-κB (NF-κB) down-regulation in macrophages. Vasostatin-1 suppressed oxidized low-density lipoprotein (oxLDL)-induced foam cell formation associated with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) and CD36 down-regulation and ATP-binding cassette transporter A1 (ABCA1) up-regulation in macrophages. In HASMCs, vasostatin-1 suppressed angiotensin II (AngII)-induced migration and collagen-3 and fibronectin expression via decreasing ERK1/2 and p38 phosphorylation, but increased elastin expression and matrix metalloproteinase (MMP)-2 and MMP-9 activities via increasing Akt and JNK phosphorylation. Vasostatin-1 did not affect the proliferation and apoptosis in HASMCs. Four-week infusion of vasostatin-1 suppressed the development of aortic atherosclerotic lesions with reductions in intra-plaque inflammation, macrophage infiltration, and SMC content, and plasma glucose level in ApoE−/− mice. These results indicate the inhibitory effects of vasostatin-1 against atherogenesis. The present study provided the first evidence that vasostatin-1 may serve as a novel therapeutic target for atherosclerosis.

Download Full-text

Abstract 633: Macrophage SR-BI Suppresses Atherosclerosis by Modulation of Autophagy via VPS34/Belclin-1 Pathway

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.633 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Huan Tao ◽

Patricia G Yancey ◽

John L Blakemore ◽

Youmin Zhang ◽

Lei Ding ◽

...

Keyword(s):

Foam Cell ◽

Oxidized Ldl ◽

Cell Formation ◽

Atherosclerotic Lesion ◽

Beclin 1 ◽

Foam Cell Formation ◽

Aortic Tissue ◽

Type I ◽

Macrophage Foam Cell ◽

Atherosclerotic Lesions

Background: Autophagy modulates vascular cell lipid metabolism, lipid droplet turnover, foam cell formation, cell survival and death, and inflammation. Scavenger receptor class B type I (SR-BI) deficiency causes impaired lysosome function in macrophages and erythrocytes. Methods and Results: Bone marrow transplantation studies were performed in ApoE and LDLR deficient mice to examine the effects of hematopoietic SR-BI deletion on atherosclerotic lesion autophagy. In addition, in vitro studies compared WT versus SR-BI -/- macrophages. Under conditions of cholesterol induced stress, the mRNA and protein levels of critical autophagy players including ATG5, ATG6/Belcin-1, ATG7 and LC3II were decreased by 37.8% to 84.6% (P<0.05 to 0.01) in SR-B1 -/- macrophages and atherosclerotic aortic tissue compared to controls. Electron microscopic analysis showed that SR-BI -/- versus WT macrophages had 80% fewer (P<0.05) autophagsomes in response to cholesterol enrichment. Macrophage SR-BI deficiency led to 1.8-fold (P<0.05) more lipid deposition and 2.5-fold more (P<0.01) apoptosis in response to oxidized LDL. Furthermore, hematopoietic SR-BI deletion caused 2.3 fold (P<0.05) more cell death in aortic atherosclerotic lesions compared to the WT control. Pharmacologic activation of autophagy did not reduce the levels of lipid droplets or cell apoptosis in SR-BI null macrophages vs WT control. WT peritoneal macrophages were used to examine SR-BI subcellular distribution and its interaction with VPS34/Beclin-1. In response to induction of autophagy, macrophage SR-BI was expressed in lysosomes and co-localized with LC3-II. Furthermore, we found that SR-BI directly interacted with the VPS34/Beclin-1 complex. Conclusions: SR-BI deficiency leads to defective autophagy and accelerates macrophage foam cell formation and apoptosis in experimental mouse atherosclerotic lesions. Macrophage SR-BI regulates expression of critical autophagy players and directly modulates autophagy via the VPS34/Beclin-1 pathway, identifying novel targets for the treatment of atherosclerosis.

Download Full-text

WO10-OR-6 COMBINED DELETION OF SR-BI AND ABCA1 IN MACROPHAGES DRAMATICALLY ENHANCES MACROPHAGE FOAM CELL FORMATION AND ATHEROSCLEROTIC LESION DEVELOPMENT

Atherosclerosis Supplements ◽

10.1016/s1567-5688(07)70986-8 ◽

2007 ◽

Vol 8 (1) ◽

pp. 11

Author(s):

M. Pennings ◽

R.B. Hildebrand ◽

G. Chimini ◽

T.J. Van Berkel ◽

M. Van Eck

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Atherosclerotic Lesion ◽

Foam Cell Formation ◽

Macrophage Foam Cell ◽

Lesion Development ◽

Atherosclerotic Lesion Development

Download Full-text

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

The Journal of Lipid Research ◽

10.1194/jlr.m082651 ◽

2018 ◽

Vol 59 (4) ◽

pp. 658-669 ◽

Cited By ~ 9

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.

Download Full-text

Salusins: Potential Use as a Biomarker for Atherosclerotic Cardiovascular Diseases

International Journal of Hypertension ◽

10.1155/2013/965140 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 21

Author(s):

Kengo Sato ◽

Rena Watanabe ◽

Fumiko Itoh ◽

Masayoshi Shichiri ◽

Takuya Watanabe

Keyword(s):

Cardiovascular Diseases ◽

Vascular Tissue ◽

Inflammatory Responses ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Human Macrophage ◽

Central Administration ◽

Macrophage Foam Cell ◽

Atherosclerotic Cardiovascular Diseases

Human salusin-αand salusin-βare related peptides produced from prosalusin. Bolus injection of salusin-βinto rats induces more profound hypotension and bradycardia than salusin-α. Central administration of salusin-βincreases blood pressure via release of norepinephrine and arginine-vasopressin. Circulating levels of salusin-αand salusin-βare lower in patients with essential hypertension. Salusin-βexerts more potent mitogenic effects on human vascular smooth muscle cells (VSMCs) and fibroblasts than salusin-α. Salusin-βaccelerates inflammatory responses in human endothelial cells and monocyte-endothelial adhesion. Human macrophage foam cell formation is stimulated by salusin-βbut suppressed by salusin-α. Chronic salusin-βinfusion into apolipoprotein E-deficient mice enhances atherosclerotic lesions; salusin-αinfusion reduces lesions. Salusin-βis expressed in proliferative neointimal lesions of porcine coronary arteries after stenting. Salusin-αand salusin-βimmunoreactivity have been detected in human coronary atherosclerotic plaques, with dominance of salusin-βin macrophage foam cells, VSMCs, and fibroblasts. Circulating salusin-βlevels increase and salusin-αlevels decrease in patients with coronary artery disease. These findings suggest that salusin-βand salusin-αmay contribute to proatherogenesis and antiatherogenesis, respectively. Increased salusin-βand/or decreased salusin-αlevels in circulating blood and vascular tissue are closely linked with atherosclerosis. Salusin-αand salusin-βcould be candidate biomarkers and therapeutic targets for atherosclerotic cardiovascular diseases.

Download Full-text

Faculty Opinions recommendation of A CD36-dependent signaling cascade is necessary for macrophage foam cell formation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1040613.489620 ◽

2006 ◽

Author(s):

Axel Nohturfft

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Signaling Cascade ◽

Foam Cell Formation ◽

Macrophage Foam Cell

Download Full-text

Dynamic Role of Macrophage Sub Types for Development of Atherosclerosis and Potential Use of Herbal Immunomodulators as Imminent Therapeutic Strategy

Cardiovascular & Hematological Agents in Medicinal Chemistry ◽

10.2174/1871525718666201217163207 ◽

2020 ◽

Vol 18 ◽

Author(s):

Parimalanandhini Duraisamy ◽

Sangeetha Ravi ◽

Mahalakshmi Krishnan ◽

Catherene M. Livya ◽

Beulaja Manikandan ◽

...

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Atherosclerotic Lesion ◽

Foam Cell Formation ◽

Atherosclerosis Progression ◽

Proinflammatory Mediators ◽

M1 Macrophage ◽

Tnf Α ◽

Inflammatory Site

: Atherosclerosis, a major contributor to cardiovascular disease is a global alarm causing mortality worldwide. Being a progressive disease in the arteries, it mainly causes recruitment of monocytes to the inflammatory sites and subside pathological conditions. Monocyte-derived macrophage mainly acts in foam cell formation by engorging the LDL molecules, oxidizes it into Ox-LDL and leads to plaque deposit development. Macrophages in general differentiate, proliferate and undergo apoptosis at the inflammatory site. Frequently two subtypes of macrophages M1 and M2 has to act crucially in balancing the micro-environmental conditions of endothelial cells in arteries. The productions of proinflammatory mediators like IL-1, IL-6, TNF-α by M1 macrophage has atherogenic properties majorly produced during the early progression of atherosclerotic plaques. To counteract cytokine productions and M1-M2 balance, secondary metabolites (phytochemicals) from plants act as a therapeutic agent in alleviating atherosclerosis progression. This review summarizes the fundamental role of the macrophage in atherosclerotic lesion formation along with its plasticity characteristic as well as recent therapeutic strategies using herbal components and anti-inflammatory cytokines as potential immunomodulators.

Download Full-text

Glucose-Dependent Insulinotropic Polypeptide Suppresses Foam Cell Formation of Macrophages through Inhibition of the Cyclin-Dependent Kinase 5-CD36 Pathway

Biomedicines ◽

10.3390/biomedicines9070832 ◽

2021 ◽

Vol 9 (7) ◽

pp. 832

Author(s):

Michishige Terasaki ◽

Hironori Yashima ◽

Yusaku Mori ◽

Tomomi Saito ◽

Yoshie Shiraga ◽

...

Keyword(s):

Gene Expression ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

U937 Cells ◽

Cyclin Dependent Kinase ◽

Macrophage Foam Cell ◽

Cyclin Dependent Kinase 5 ◽

Gip Receptor ◽

Cd36 Gene

Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an atheroprotective property in animal models. However, the effect of GIP on macrophage foam cell formation, a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on foam cell formation of, and CD36 expression in, macrophages extracted from GIP receptor-deficient (Gipr−/−) and Gipr+/+ mice and cultured human U937 macrophages by using an agonist for GIP receptor, [D-Ala2]GIP(1–42). Foam cell formation evaluated by esterification of free cholesterol to cholesteryl ester and CD36 gene expression in macrophages isolated from Gipr+/+ mice infused subcutaneously with [D-Ala2]GIP(1–42) were significantly suppressed compared with vehicle-treated mice, while these beneficial effects were not observed in macrophages isolated from Gipr−/− mice infused with [D-Ala2]GIP(1–42). When macrophages were isolated from Gipr+/+ and Gipr−/− mice, and then exposed to [D-Ala2]GIP(1–42), similar results were obtained. [D-Ala2]GIP(1–42) attenuated ox-LDL uptake of, and CD36 gene expression in, human U937 macrophages as well. Gene expression level of cyclin-dependent kinase 5 (Cdk5) was also suppressed by [D-Ala2]GIP(1–42) in U937 cells, which was corelated with that of CD36. A selective inhibitor of Cdk5, (R)-DRF053 mimicked the effects of [D-Ala2]GIP(1–42) in U937 cells. The present study suggests that GIP could inhibit foam cell formation of macrophages by suppressing the Cdk5-CD36 pathway via GIP receptor.

Download Full-text