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

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.

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

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takuya Watanabe ◽  
Yoshitaka Iso ◽  
Shinji Koba ◽  
Tetsuo Sakai ◽  
Gang Xu ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Apolipoprotein A1 ◽  
Foam Cell Formation ◽  
Type I ◽  
Macrophage Foam Cell ◽  
Human Macrophages ◽  
Coronary Syndrome ◽  
Atherosclerotic Lesions ◽  
Mild Hypertensive

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.

Inhibitory effects of vasostatin-1 against atherogenesis

2018 ◽  
Vol 132 (23) ◽  
pp. 2493-2507 ◽  
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.

scholarly journals Anti-Atherosclerotic Activity of (3R)-5-Hydroxymellein from an Endophytic Fungus Neofusicoccum parvum JS-0968 Derived from Vitex rotundifolia through the Inhibition of Lipoproteins Oxidation and Foam Cell Formation

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 715
Author(s):  
Jae-Yong Kim ◽  
Soonok Kim ◽  
Sang Hee Shim
Keyword(s):  
Conformational Changes ◽  
Endophytic Fungus ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Ldl Oxidation ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Neofusicoccum Parvum

An endophytic fungus, Neofusicoccum parvum JS-0968, was isolated from a plant, Vitex rotundifolia. The chemical investigation of its cultures led to the isolation of a secondary metabolite, (3R)-5-hydroxymellein. It has been reported to have antifungal, antibacterial, and antioxidant activity, but there have been no previous reports on the effects of (3R)-5-hydroxymellein on atherosclerosis. The oxidation of lipoproteins and foam cell formation have been known to be significant in the development of atherosclerosis. Therefore, we investigated the inhibitory effects of (3R)-5-hydroxymellein on atherosclerosis through low-density lipoprotein (LDL) and high-density lipoprotein (HDL) oxidation and macrophage foam cell formation. LDL and HDL oxidation were determined by measuring the production of conjugated dienes and malondialdehyde, the amount of hyperchromicity and carbonyl content, conformational changes, and anti-LDL oxidation. In addition, the inhibition of foam cell formation was measured by Oil red O staining. As a result, (3R)-5-hydroxymellein suppressed the oxidation of LDL and HDL through the inhibition of lipid peroxidation, the decrease of negative charges, the reduction of hyperchromicity and carbonyl contents, and the prevention of apolipoprotein A-I (ApoA-I) aggregation and apoB-100 fragmentation. Furthermore, (3R)-5-hydroxymellein significantly reduced foam cell formation induced by oxidized LDL (oxLDL). Taken together, our data show that (3R)-5-hydroxymellein could be a potential preventive agent for atherosclerosis via obvious anti-LDL and HDL oxidation and the inhibition of foam cell formation.

Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation

2011 ◽  
Vol 106 (11) ◽  
pp. 763-771 ◽  
Author(s):  
Ine Wolfs ◽  
Marjo Donners ◽  
Menno de Winther
Keyword(s):  
Inflammatory Cell ◽  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
M1 Macrophages ◽  
Macrophage Polarisation ◽  
Atherosclerotic Lesions ◽  
Differentiation Factors

SummaryThe phenotype of macrophages in atherosclerotic lesions can vary dramatically, from a large lipid laden foam cell to a small inflammatory cell. Classically, the concept of macrophage heterogeneity discriminates between two extremes called either pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Polarisation of plaque macrophages is predominantly determined by the local micro-environment present in the atherosclerotic lesion and is rather more complex than typically described by the M1/M2 paradigm. In this review we will discuss the role of various polarising factors in regulating the phenotypical state of plaque macrophages. We will focus on two main levels of phenotype regulation, one determined by differentiation factors produced in the lesion and the other determined by T-cell-derived polarising cytokines. With foam cell formation being a key characteristic of macrophages during atherosclerosis initiation and progression, these polarisation factors will also be linked to lipid handling of macrophages.

scholarly journals Role of pyruvate kinase M2 in oxidized LDL-induced macrophage foam cell formation and inflammation

2020 ◽  
Vol 61 (3) ◽  
pp. 351-364 ◽  
Author(s):  
Amit Kumar ◽  
Priya Gupta ◽  
Minakshi Rana ◽  
Tulika Chandra ◽  
Madhu Dikshit ◽  
...  
Keyword(s):  
Protein Expression ◽  
Pyruvate Kinase ◽  
Foam Cell ◽  
Aerobic Glycolysis ◽  
Oxidized Ldl ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Macrophage Foam Cell ◽  
Pyruvate Kinase M2

Pyruvate kinase M2 (PKM2) links metabolic and inflammatory dysfunction in atherosclerotic coronary artery disease; however, its role in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation is unknown and therefore was studied. In recombinant mouse granulocyte-macrophage colony-stimulating factor-differentiated murine bone marrow-derived macrophages, early (1–6 h) Ox-LDL treatment induced PKM2 tyrosine 105 phosphorylation and promotes its nuclear localization. PKM2 regulates aerobic glycolysis and inflammation because PKM2 shRNA or Shikonin abrogated Ox-LDL-induced hypoxia-inducible factor-1α target genes lactate dehydrogenase, glucose transporter member 1, interleukin 1β (IL-1β) mRNA expression, lactate, and secretory IL-1β production. PKM2 inhibition significantly increased Ox-LDL-induced ABCA1 and ABCG1 protein expression and NBD-cholesterol efflux to apoA1 and HDL. PKM2 shRNA significantly inhibited Ox-LDL-induced CD36, FASN protein expression, DiI-Ox-LDL binding and uptake, and cellular total cholesterol, free cholesterol, and cholesteryl ester content. Therefore, PKM2 regulates lipid uptake and efflux. DASA-58, a PKM2 activator, downregulated LXR-α, ABCA1, and ABCG1, and augmented FASN and CD36 protein expression. Peritoneal macrophages showed similar results. Ox-LDL induced PKM2- SREBP-1 interaction and FASN expression in a PKM2-dependent manner. Therefore, this study suggests a role for PKM2 in Ox-LDL-induced aerobic glycolysis, inflammation, and macrophage foam cell formation.

Abstract 333: CD36 Mediates Cholesterol Uptake via Na/K-ATPase/lyn Signaling in Macrophages

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Yiliang Chen ◽  
David Kennedy ◽  
Zhichuan Li ◽  
Zijian Xie ◽  
Roy L Silverstein
Keyword(s):  
Kinase Activity ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Scavenger Receptor ◽  
Cell Formation ◽  
Developed Countries ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Cholesterol Uptake ◽  
Lyn Kinase

Atherosclerosis, the leading cause of death in the developed countries, is characterized by macrophage foam cell formation. We previously showed that CD36, a scavenger receptor highly expressed in macrophages, mediates oxidized-LDL uptake, contributes to intracellular cholesterol accumulation and foam cell formation, and regulates macrophage migration and pro-inflammatory signaling. Consistently, cd36 deletion in mice protects from diet-induced atherosclerosis. Mechanistically, we discovered a novel signaling pathway, in which oxidized LDL (oxLDL) binding to CD36 activates Lyn kinase and initiates a cascade that is necessary for the pro-atherogenic cellular phenotype. How CD36 regulates Lyn kinase remains undefined. Since we previously showed that the Na/K-ATPase (NKA) regulates Src family kinases, including Lyn, we hypothesized that CD36 regulates Lyn kinase via an interaction with NKA. We used co-immunoprecipitation, FRET, and a novel cross linking assay to demonstrate that CD36 physically associates with NKA on the macrophage surface. Using a Lyn kinase activity assay, we showed that the interaction regulates Lyn kinase activity in response to oxLDL in macrophages. Moreover, a newly developed peptide inhibitor specifically blocked Lyn activation in response to oxLDL and attenuated oxLDL-stimulated cholesterol uptake (135.6±3.4 μM cholesterol/mg protein after 24 hours vs 173.8±7.7 μM cholesterol/mg protein in vehicle treated cells; p=0.0005; n=6). Taken together, we conclude that CD36 signals through NKA to regulate Lyn kinase activity in macrophages, which may be a molecular mechanism underlying cholesterol overloading and foam cell formation.

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