Abstract 3758: Preventive Effects of Heregulin-Beta1 on Macrophage Foam Cell Formation and Atherosclerosis

Human heregulins, neuregulin-1 type I polypeptides known to activate proliferation, differentiation, and survival of glial cells, neurons, and myocytes, were recently found to be expressed in macrophage foam cells within human coronary atherosclerotic lesions. Macrophage foam cell formation, characterized by cholesterol ester (CE) accumulation, is modulated by scavenger receptor class A (SR-A), acyl-CoA:cholesterol acyltransferase-1 (ACAT1), and ATP-binding cassette transporter A1 (ABCA1). The present study clarified the functional roles of heregulins in macrophage foam cell formation and atherosclerosis. Plasma heregulin-beta1 levels were significantly decreased in 31 patients with acute coronary syndrome (ACS) and 33 patients with stable angina pectoris as compared with 34 mild hypertensive patients and 40 healthy volunteers (1.3+/−0.3, 2.0+/−0.4 versus 7.6+/−1.4, 8.2+/−1.2 ng/mL; at least P < 0.01). Immunoreactive heregulins and these receptor c-erbB3 were detectable within human coronary atherothrombosis obtained from ACS patients. In primary cultured human monocyte-macrophages, the expression of endogenous heregulins, heregulin-beta1, and c-erbB3 increased during monocytic differentiation into macrophages. In human macrophages differentiated by 7-day culture, exogenous heregulin-beta1, but not heregulin-alpha, significantly reduced acetylated low-density lipoprotein (acLDL)-induced CE accumulation by reducing SR-A and ACAT1 expression and by increasing ABCA1 expression at both mRNA and protein levels. Heregulin-beta1 significantly decreased endocytic uptake of [ 125 I]acLDL and increased cholesterol efflux by apolipoprotein A1 from human macrophages. Chronic infusion of heregulin-beta1 by osmotic mini-pumps into apolipoprotein E-deficient mice significantly suppressed the progression of macrophage-driven atherosclerotic lesions by 64%. Our study provides the first evidence that heregulin-beta1 may participate in anti-atherogenesis by suppressing macrophage foam cell formation via SR-A and ACAT1 down-regulation and ABCA1 up-regulation.

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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.

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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.

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A Novel Family of Atherogenic Oxidized Phospholipids Promotes Macrophage Foam Cell Formation via the Scavenger Receptor CD36 and Is Enriched in Atherosclerotic Lesions

Journal of Biological Chemistry ◽

10.1074/jbc.m205924200 ◽

2002 ◽

Vol 277 (41) ◽

pp. 38517-38523 ◽

Cited By ~ 262

Author(s):

Eugene A. Podrez ◽

Eugenia Poliakov ◽

Zhongzhou Shen ◽

Renliang Zhang ◽

Yijun Deng ◽

...

Keyword(s):

Foam Cell ◽

Scavenger Receptor ◽

Cell Formation ◽

Foam Cell Formation ◽

Oxidized Phospholipids ◽

Macrophage Foam Cell ◽

Atherosclerotic Lesions

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Blockade of Macrophage CD147 Protects Against Foam Cell Formation in Atherosclerosis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.609090 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jian-Jun Lv ◽

Hao Wang ◽

Hong-Yong Cui ◽

Ze-Kun Liu ◽

Ren-Yu Zhang ◽

...

Keyword(s):

Foam Cell ◽

Scavenger Receptor ◽

Cell Formation ◽

Foam Cell Formation ◽

Macrophage Foam Cell ◽

Atherosclerotic Lesions ◽

Cd147 Expression ◽

Compound Screening ◽

Genetic Deletion ◽

Atherosclerosis Development

The persistence of macrophage-derived foam cells in the artery wall fuels atherosclerosis development. However, the mechanism of foam cell formation regulation remains elusive. We are committed to determining the role that CD147 might play in macrophage foam cell formation during atherosclerosis. In this study, we found that CD147 expression was primarily increased in mouse and human atherosclerotic lesions that were rich in macrophages and could be upregulated by ox-LDL. High-throughput compound screening indicated that ox-LDL-induced CD147 upregulation in macrophages was achieved through PI3K/Akt/mTOR signaling. Genetic deletion of macrophage CD147 protected against foam cell formation by impeding cholesterol uptake, probably through the scavenger receptor CD36. The opposite effect was observed in primary macrophages isolated from macrophage-specific CD147-overexpressing mice. Moreover, bioinformatics results indicated that CD147 suppression might exert an atheroprotective effect via various processes, such as cholesterol biosynthetic and metabolic processes, LDL and plasma lipoprotein clearance, and decreased platelet aggregation and collagen degradation. Our findings identify CD147 as a potential target for prevention and treatment of atherosclerosis in the future.

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Aged Garlic Extract Inhibits CD36 Expression and Foam Cell Formation in Human Macrophages

Planta Medica ◽

10.1055/s-2007-987237 ◽

2007 ◽

Vol 73 (09) ◽

Author(s):

N Ide ◽

N Morihara ◽

L Paptheodorou ◽

R Stirner ◽

N Weiss

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Garlic Extract ◽

Foam Cell Formation ◽

Aged Garlic Extract ◽

Human Macrophages ◽

Cd36 Expression ◽

Aged Garlic

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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

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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.

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