scholarly journals Emerging Roles of Cardiotrophin-1 in the Pathogenesis and Biomarker of Atherosclerosis

J ◽  
2018 ◽  
Vol 1 (1) ◽  
pp. 94-105 ◽  
Author(s):  
Takuya Watanabe ◽  
Hanae Konii ◽  
Kengo Sato
Keyword(s):  
Heart Failure ◽  
Heart Disease ◽  
Cardiac Hypertrophy ◽  
Foam Cell ◽  
Vascular Endothelial Cells ◽  
Cell Formation ◽  
Hypertensive Heart Disease ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Atheromatous Plaques

Cardiotrophin-1 (CT-1), an interleukin-6 family cytokine, is known as an active inducer capable of cardiac hypertrophy and vascular stiffness in hypertensive heart disease. CT-1 is expressed at high levels in the heart, vascular endothelial cells (ECs), and adipocytes. CT-1 stimulates inflammatory and proatherogenic molecule expression in human monocytes and ECs, as well as monocyte-EC adhesion. CT-1 enhances oxidized low-density lipoprotein-induced foam-cell formation in human monocyte-derived macrophages. CT-1 stimulates the migration, proliferation, and colloagen-1 production in human vascular smooth muscle cells. Chronic CT-1 infusion into Apoe−/− mice accelerates the development of aortic atherosclerotic lesions. CT-1 is expressed at high levels in ECs and macrophage foam cells within atheromatous plaques in Apoe−/− mice. A blockade of CT-1 using anti-CT-1 neutralizing antibody results in the prevention of atherogenesis in Apoe−/− mice. Plasma CT-1 concentrations are elevated in patients with hypertensive heart disease, ischemic heart disease, and metabolic syndrome, and are positively associated with the severity of cardiac hypertrophy, heart failure, and atherosclerosis. Increased plasma concentration of CT-1 is a predictor of death and heart failure following acute myocardial infarction. Therefore, CT-1 serves a novel therapeutic target for atherosclerosis and related diseases. Plasma CT-1 may be a reliable biomarker for atherosclerotic cardiovascular diseases.

scholarly journals Neutrophils as a Novel Target of Modified Low-Density Lipoproteins and an Accelerator of Cardiovascular Diseases

2020 ◽  
Vol 21 (21) ◽  
pp. 8312
Author(s):  
Takashi Obama ◽  
Hiroyuki Itabe
Keyword(s):  
Cardiovascular Diseases ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Vascular Endothelial Cells ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Foam Cell Formation ◽  
Low Density

Neutrophil extracellular traps (NETs) significantly contribute to various pathophysiological conditions, including cardiovascular diseases. NET formation in the vasculature exhibits inflammatory and thrombogenic activities on the endothelium. NETs are induced by various stimulants such as exogenous damage-associated molecular patterns (DAMPs). Oxidatively modified low-density lipoprotein (oxLDL) has been physiologically defined as a subpopulation of LDL that comprises various oxidative modifications in the protein components and oxidized lipids, which could act as DAMPs. oxLDL has been recognized as a crucial initiator and accelerator of atherosclerosis through foam cell formation by macrophages; however, recent studies have demonstrated that oxLDL stimulates neutrophils to induce NET formation and enhance NET-mediated inflammatory responses in vascular endothelial cells, thereby suggesting that oxLDL may be involved in cardiovascular diseases through neutrophil activation. As NETs comprise myeloperoxidase and proteases, they have the potential to mediate oxidative modification of LDL. This review summarizes recent updates on the analysis of NETs, their implications for cardiovascular diseases, and prospects for a possible link between NET formation and oxidative modification of lipoproteins.

Chemerin-9, a potent agonist of chemerin receptor (ChemR23), prevents atherogenesis

2019 ◽  
Vol 133 (16) ◽  
pp. 1779-1796 ◽  
Author(s):  
Kengo Sato ◽  
Hayami Yoshizawa ◽  
Tomomi Seki ◽  
Remina Shirai ◽  
Tomoyuki Yamashita ◽  
...  
Keyword(s):  
Coronary Arteries ◽  
Foam Cell ◽  
Umbilical Vein ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Tnf Α ◽  
Atheromatous Plaques

Abstract Plasma levels of chemerin, an adipocytokine produced from the adipose tissues and liver, are associated with metabolic syndrome and coronary artery disease (CAD). Chemerin and its analog, chemerin-9, are known to bind to their receptor, ChemR23. However, whether chemerin and chemerin-9 affect atherogenesis remains to be elucidated. We investigated the expression of chemerin and ChemR23 in human coronary arteries and cultured human vascular cells. The effects of chemerin and chemerin-9 on atheroprone phenomena were assessed in human THP1 monocytes, human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs) and aortic lesions in Apoe−/− mice. In patients with CAD, a small amount of ChemR23, but not chemerin, was expressed within atheromatous plaques in coronary arteries. Chemerin and ChemR23 were expressed at high levels in THP1 monocytes, THP1-derived macrophages, and HUVECs; however, their expression in HASMCs was weak. Chemerin and chemerin-9 significantly suppressed the tumor necrosis factor-α (TNF-α)-induced mRNA expression of adhesion and pro-inflammatory molecules in HUVECs. Chemerin and chemerin-9 significantly attenuated the TNF-α-induced adhesion of THP1 monocytes to HUVECs and macrophage inflammatory phenotype. Chemerin and chemerin-9 suppressed oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cell formation associated with down-regulation of CD36 and up-regulation of ATP-binding cassette transporter A1 (ABCA1). In HASMCs, chemerin and chemerin-9 significantly suppressed migration and proliferation without inducing apoptosis. In the Apoe−/− mice, a 4-week infusion of chemerin-9 significantly decreased the areas of aortic atherosclerotic lesions by reducing intraplaque macrophage and SMC contents. Our results indicate that chemerin-9 prevents atherosclerosis. Therefore, the development of chemerin analogs/ChemR23 agonists may serve as a novel therapeutic target for atherosclerotic diseases.

ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

2021 ◽  
pp. 107424842110236
Author(s):  
Dun Niu ◽  
Lanfang Li ◽  
Zhizhong Xie
Keyword(s):  
Therapeutic Target ◽  
Chloride Channels ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Molecular Structures ◽  
Foam Cell Formation ◽  
Endothelium Dysfunction ◽  
Atherosclerotic Process

Chloride channel 3 (ClC-3), a Cl−/H+ antiporter, has been well established as a member of volume-regulated chloride channels (VRCCs). ClC-3 may be a crucial mediator for activating inflammation-associated signaling pathways by regulating protein phosphorylation. A growing number of studies have indicated that ClC-3 overexpression plays a crucial role in mediating increased plasma low-density lipoprotein levels, vascular endothelium dysfunction, pro-inflammatory activation of macrophages, hyper-proliferation and hyper-migration of vascular smooth muscle cells (VSMCs), as well as oxidative stress and foam cell formation, which are the main factors responsible for atherosclerotic plaque formation in the arterial wall. In the present review, we summarize the molecular structures and classical functions of ClC-3. We further discuss its emerging role in the atherosclerotic process. In conclusion, we explore the potential role of ClC-3 as a therapeutic target for atherosclerosis.

scholarly journals Protective Effect of Lusianthridin on Hemin-Induced Low-Density Lipoprotein Oxidation

2021 ◽  
Vol 14 (6) ◽  
pp. 567
Author(s):  
Su Wutyi Thant ◽  
Noppawan Phumala Morales ◽  
Visarut Buranasudja ◽  
Boonchoo Sritularak ◽  
Rataya Luechapudiporn
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Raw 264.7 ◽  
Low Density ◽  
Lipoprotein Oxidation ◽  
Raw 264.7 Macrophage Cells ◽  
Low Density Lipoprotein Oxidation

Oxidation of low-density lipoprotein (LDL) plays a crucial role in the pathogenesis of atherosclerosis. Hemin (iron (III)-protoporphyrin IX) is a degradation product of hemoglobin that can be found in thalassemia patients. Hemin is a strong oxidant that can cause LDL oxidation and contributes to atherosclerosis in thalassemia patients. Lusianthridin from Dendrobium venustrum is a phenolic compound that possesses antioxidant activity. Hence, lusianthridin could be a promising compound to be used against hemin-induced oxidative stress. The major goal of this study is to evaluate the protective effect of lusianthridin on hemin-induced low-density lipoprotein oxidation (he-oxLDL). Here, various concentrations of lusianthridin (0.25, 0.5, 1, and 2 µM) were preincubated with LDL for 30 min, then 5 µM of hemin was added to initiate the oxidation, and oxidative parameters were measured at various times of incubation (0, 1, 3, 6, 12, 24 h). Lipid peroxidation of LDL was measured by thiobarbituric reactive substance (TBARs) assay and relative electrophoretic mobility (REM). The lipid composition of LDL was analyzed by using reverse-phase HPLC. Foam cell formation with he-oxLDL in RAW 264.7 macrophage cells was detected by Oil Red O staining. The results indicated that lusianthridin could inhibit TBARs formation, decrease REM, decrease oxidized lipid products, as well as preserve the level of cholesteryl arachidonate and cholesteryl linoleate. Moreover, He-oxLDL incubated with lusianthridin for 24 h can reduce the foam cell formation in RAW 264.7 macrophage cells. Taken together, lusianthridin could be a potential agent to be used to prevent atherosclerosis in thalassemia patients.

scholarly journals Structure and Dynamics of Oxidized Lipoproteins In Vivo: Roles of High-Density Lipoprotein

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 655
Author(s):  
Hiroyuki Itabe ◽  
Naoko Sawada ◽  
Tomohiko Makiyama ◽  
Takashi Obama
Keyword(s):  
Cardiovascular Diseases ◽  
High Density Lipoprotein ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
High Density ◽  
Oxidative Modification ◽  
Foam Cell Formation ◽  
Oxidized Lipoproteins

Oxidative modification of lipoproteins is implicated in the occurrence and development of atherosclerotic lesions. Earlier studies have elucidated on the mechanisms of foam cell formation and lipid accumulation in these lesions, which is mediated by scavenger receptor-mediated endocytosis of oxidized low-density lipoprotein (oxLDL). Mounting clinical evidence has supported the involvement of oxLDL in cardiovascular diseases. High-density lipoprotein (HDL) is known as anti-atherogenic; however, recent studies have shown circulating oxidized HDL (oxHDL) is related to cardiovascular diseases. A modified structure of oxLDL, which was increased in the plasma of patients with acute myocardial infarction, was characterized. It had two unique features: (1) a fraction of oxLDL accompanied oxHDL, and (2) apoA1 was heavily modified, while modification of apoB, and the accumulation of oxidized phosphatidylcholine (oxPC) and lysophosphatidylcholine (lysoPC) was less pronounced. When LDL and HDL were present at the same time, oxidized lipoproteins actively interacted with each other, and oxPC and lysoPC were transferred to another lipoprotein particle and enzymatically metabolized rapidly. This brief review provides a novel view on the dynamics of oxLDL and oxHDL in circulation.

Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christina Grothusen ◽  
Harald Schuett ◽  
Stefan Lumpe ◽  
Andre Bleich ◽  
Silke Glage ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

Abstract 43: Cholesterol Efflux Pathways Suppress Inflammasome Activation in Mice and Humans

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Marit Westerterp ◽  
Panagiotis Fotakis ◽  
Mireille Ouimet ◽  
Andrea E Bochem ◽  
Hanrui Zhang ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Inflammasome Activation ◽  
Loss Of Function ◽  
Caspase 1 ◽  
Macrophage Cholesterol Efflux

Plasma high-density-lipoprotein (HDL) has several anti-atherogenic properties, including its key role in functioning as acceptor for ATP-binding cassette A1 and G1 (ABCA1 and ABCG1) mediated cholesterol efflux. We have shown previously that macrophage Abca1/g1 deficiency accelerates atherosclerosis, by enhancing foam cell formation and inflammatory cytokine expression in atherosclerotic plaques. Macrophage cholesterol accumulation activates the inflammasome, leading to caspase-1 cleavage, required for IL-1β and IL-18 secretion. Several studies have suggested that inflammasome activation accelerates atherogenesis. We hypothesized that macrophage Abca1/g1 deficiency activates the inflammasome. In Ldlr -/- mice fed a Western type diet (WTD), macrophage Abca1/g1 deficiency increased IL-1β and IL-18 plasma levels (2-fold; P <0.001), and induced caspase-1 cleavage. Deficiency of the inflammasome components Nlrp3 or caspase-1 in macrophage Abca1/g1 knockouts reversed the increase in plasma IL-18 levels ( P <0.001), indicating these changes were inflammasome dependent. We found that macrophage Abca1/g1 deficiency induced caspase-1 cleavage in splenic CD115 + monocytes and CD11b + macrophages. While mitochondrial ROS production or lysosomal function were not affected, macrophage Abca1/g1 deficiency led to an increased splenic population of monocytes (2.5-fold; P <0.01). Monocytes secrete ATP, and as a result, ATP secretion from total splenic cells was increased (2.5-fold; P <0.01), likely contributing to inflammasome activation. Caspase-1 deficiency decreased atherosclerosis in macrophage Abca1/g1 deficient Ldlr -/- mice fed WTD for 8 weeks (225822 vs 138606 μm 2 ; P <0.05). Of therapeutic interest, one injection of reconstituted HDL (100 mg/kg) in macrophage Abca1/g1 knockouts decreased plasma IL-18 levels ( P <0.05). Tangier disease patients, with a homozygous loss-of-function for ABCA1, showed increased IL-1β and IL-18 plasma levels (3-fold; P <0.001), suggesting that cholesterol efflux pathways also suppress inflammasome activation in humans. These findings suggest that macrophage cholesterol efflux pathways suppress inflammasome activation, possibly contributing to the anti-atherogenic effects of HDL treatment.

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 Epac1 regulates cellular SUMOylation by promoting the formation of SUMO-activating nuclear condensates

2022 ◽  
Author(s):  
Wenli Yang ◽  
William G Robichaux ◽  
Fang C Mei ◽  
Wel Lin ◽  
Li Li ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Stress Responses ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cellular Stress ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Intracellular Camp ◽  
Protein Sumoylation

Protein SUMOylation plays an essential role in maintaining cellular homeostasis when cells are under stress. However, precisely how SUMOylation is regulated, and a molecular mechanism linking cellular stress to SUMOylation remains elusive. Herein, we report that cAMP, a major stress-response second messenger, acts through Epac1 as a regulator of cellular SUMOylation. The Epac1-associated proteome is highly enriched with components of the SUMOylation pathway. Activation of Epac1 by intracellular cAMP triggers phase separation and the formation of nuclear condensates containing Epac1 and general components of the SUMOylation machinery to promote cellular SUMOylation. Furthermore, genetic knockout of Epac1 obliterates oxidized low-density lipoprotein induced cellular SUMOylation in macrophages, leading to suppression of foam cell formation. These results provide a direct nexus connecting two major cellular stress responses to define a molecular mechanism in which cAMP regulates the dynamics of cellular condensates to modulate protein SUMOylation.

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