Suppressing Macrophage Foam Cell Formation Research Articles

Associations between Vaspin Levels and Coronary Artery Disease

The relationship between serum vaspin levels and metabolic or coronary artery disease is currently of interest for researchers. Although adipokine concentrations have been shown to be increased significantly in atherosclerotic lesions, the role adipokines in the atherosclerotic process remains to be elucidated. Vaspin is a new biological marker associated with obesity and impaired insulin sensitivity. Plasma vaspin concentration has been shown to correlate with the severity of coronary artery disease. Vascular inflammation triggered by vaspin inhibits atherogenesis by suppressing macrophage foam cell formation and vascular smooth muscle cell migration and proliferation. Vaspin also contributes to plaque stabilization by increasing collagen content and reducing the intraplaque macrophage to vascular smooth muscle cell ratio. The therapeutic goal concerning vaspin is to fight atherosclerosis and related diseases, as well as to maintain vascular health.

Berberine Attenuates Cholesterol Accumulation in Macrophage Foam Cells by Suppressing AP-1 Activity and Activation of the Nrf2/HO-1 Pathway.

Atherosclerosis is a chronic inflammation condition resulting from the interaction between lipoproteins, monocyte-derived macrophages, T lymphocytes, and other cellular elements in the arterial wall. Macrophage-derived foam cells play a key role in both early and advanced stage of atherosclerosis. Previous studies have shown that berberine could inhibit foam cell formation and prevent experimental atherosclerosis. However, its underlying molecular mechanisms have not been fully clarified. In this study, we explored the cholesterol-lowering effects of berberine in macrophage-derived foam cells and investigated its possible mechanisms in prevention and treatment of atherosclerosis. Here, we demonstrated that berberine could inhibit atherosclerosis in apolipoprotein E-deficient mice and induce cholesterol reduction as well as decrease the content of macrophages. Berberine can regulate oxLDL uptake and cholesterol efflux, thus suppresses foam cell formation. Mechanisms study showed that berberine can suppress scavenger receptor expression via inhibiting the activity of AP-1 and upregulate ATP-binding cassette transporter via activating Nrf2/HO-1 signaling in human macrophage. In summary, berberine significantly inhibits atherosclerotic disease development by regulating lipid homeostasis and suppressing macrophage foam cell formation.

A Dipeptidyl Peptidase-4 Inhibitor Suppresses Macrophage Foam Cell Formation in Diabetic db/db Mice and Type 2 Diabetes Patients.

Dipeptidyl peptidase-4 (DPP-4) inhibitors could have antiatherosclerotic action, in addition to antihyperglycemic roles. Because macrophage foam cells are key components of atherosclerosis, we investigated the effect of the DPP-4 inhibitor teneligliptin on foam cell formation and its related gene expression levels in macrophages extracted from diabetic db/db (C57BLKS/J Iar -+Leprdb/+Leprdb) mice and type 2 diabetes (T2D) patients ex vivo. We incubated mouse peritoneal macrophages and human monocyte-derived macrophages differentiated by 7-day culture with oxidized low-density lipoprotein in the presence/absence of teneligliptin (10 nmol/L) for 18 hours. We observed remarkable suppression of foam cell formation by teneligliptin treatment ex vivo in macrophages isolated from diabetic db/db mice (32%) and T2D patients (38%); this effect was accompanied by a reduction of CD36 (db/db mice, 43%; T2D patients, 46%) and acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) gene expression levels (db/db mice, 47%; T2D patients, 45%). Molecular mechanisms underlying this effect are associated with downregulation of CD36 and ACAT-1 by teneligliptin. The suppressive effect of a DPP-4 inhibitor on foam cell formation in T2D is conserved across species and is worth studying to elucidate its potential as an intervention for antiatherogenesis in T2D patients.

Maslinic acid suppresses macrophage foam cell formation via inhibition of LDL oxidation and cholesterol efflux

Maslinic acid suppresses macrophage foam cell formation via inhibition of LDL oxidation and cholesterol efflux

Combination Therapy with a Sodium-Glucose Cotransporter 2 Inhibitor and a Dipeptidyl Peptidase-4 Inhibitor Additively Suppresses Macrophage Foam Cell Formation and Atherosclerosis in Diabetic Mice.

Dipeptidyl peptidase-4 inhibitors (DPP-4is), in addition to their antihyperglycemic roles, have antiatherosclerotic effects. We reported that sodium-glucose cotransporter 2 inhibitors (SGLT2is) suppress atherosclerosis in a glucose-dependent manner in diabetic mice. Here, we investigated the effects of combination therapy with SGLT2i and DPP-4i on atherosclerosis in diabetic mice. SGLT2i (ipragliflozin, 1.0 mg/kg/day) and DPP-4i (alogliptin, 8.0 mg/kg/day), either alone or in combination, were administered to db/db mice or streptozotocin-induced diabetic apolipoprotein E-null (Apoe−/−) mice. Ipragliflozin and alogliptin monotherapies improved glucose intolerance; however, combination therapy did not show further improvement. The foam cell formation of peritoneal macrophages was suppressed by both the ipragliflozin and alogliptin monotherapies and was further enhanced by combination therapy. Although foam cell formation was closely associated with HbA1c levels in all groups, DPP-4i alone or the combination group showed further suppression of foam cell formation compared with the control or SGLT2i group at corresponding HbA1c levels. Both ipragliflozin and alogliptin monotherapies decreased scavenger receptors and increased cholesterol efflux regulatory genes in peritoneal macrophages, and combination therapy showed additive changes. In diabetic Apoe−/− mice, combination therapy showed the greatest suppression of plaque volume in the aortic root. In conclusion, combination therapy with SGLT2i and DPP4i synergistically suppresses macrophage foam cell formation and atherosclerosis in diabetic mice.

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Atherosclerosis by Affecting Foam Cell Formation and Efferocytosis

Mineralocorticoid receptor (MR) has been considered as a potential target for treating atherosclerosis. However, the cellular and molecular mechanisms are not completely understood. We aim to explore the functions and mechanisms of macrophage MR in atherosclerosis. Atherosclerosis-susceptible LDLRKO chimeric mice with bone marrow cells from floxed control mice or from myeloid MR knock-out (MRKO) mice were generated and fed with high cholesterol diet. Oil red O staining showed that MRKO decreased atherosclerotic lesion area in LDLRKO mice. In another mouse model of atherosclerosis, MRKO/APOEKO mice and floxed control/APOEKO mice were generated and treated with angiotensin II. Similarly, MRKO inhibited the atherosclerotic lesion area in APOEKO mice. Histological analysis showed that MRKO increased collagen coverage and decreased necrosis and macrophage accumulation in the lesions. In vitro results demonstrated that MRKO suppressed macrophage foam cell formation and up-regulated the expression of genes involved in cholesterol efflux. Furthermore, MRKO decreased accumulation of apoptotic cells and increased effective efferocytosis in atherosclerotic lesions. In vitro study further revealed that MRKO increased the phagocytic index of macrophages without affecting their apoptosis. In conclusion, MRKO reduces high cholesterol- or angiotensin II-induced atherosclerosis and favorably changes plaque composition, likely improving plaque stability. Mechanistically, MR deficiency suppresses macrophage foam cell formation and up-regulates expression of genes related to cholesterol efflux, as well as increases effective efferocytosis and phagocytic capacity of macrophages.

Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice.

Direct associations between hyperglycemia and atherosclerosis remain unclear. We investigated the association between the amelioration of glycemia by sodium-glucose cotransporter 2 inhibitors (SGLT2is) and macrophage-driven atherosclerosis in diabetic mice. We administered dapagliflozin or ipragliflozin (1.0 mg/kg/day) for 4-weeks to apolipoprotein E-null (Apoe −/−) mice, streptozotocin-induced diabetic Apoe −/− mice, and diabetic db/db mice. We then determined aortic atherosclerosis, oxidized low-density lipoprotein (LDL)-induced foam cell formation, and related gene expression in exudate peritoneal macrophages. Dapagliflozin substantially decreased glycated hemoglobin (HbA1c) and glucose tolerance without affecting body weight, blood pressure, plasma insulin, and lipids in diabetic Apoe −/− mice. Aortic atherosclerotic lesions, atheromatous plaque size, and macrophage infiltration in the aortic root increased in diabetic Apoe −/− mice; dapagliflozin attenuated these changes by 33%, 27%, and 20%, respectively. Atherosclerotic lesions or foam cell formation highly correlated with HbA1c. Dapagliflozin did not affect atherosclerosis or plasma parameters in non-diabetic Apoe −/− mice. In db/db mice, foam cell formation increased by 4-fold compared with C57/BL6 mice, whereas ipragliflozin decreased it by 31%. Foam cell formation exhibited a strong correlation with HbA1c. Gene expression of lectin-like ox-LDL receptor-1 and acyl-coenzyme A:cholesterol acyltransferase 1 was upregulated, whereas that of ATP-binding cassette transporter A1 was downregulated in the peritoneal macrophages of both types of diabetic mice. SGLT2i normalized these gene expressions. Our study is the first to demonstrate that SGLT2i exerts anti-atherogenic effects by pure glucose lowering independent of insulin action in diabetic mice through suppressing macrophage foam cell formation, suggesting that foam cell formation is highly sensitive to glycemia ex vivo.

A glucagon-like peptide-1 analog liraglutide suppresses macrophage foam cell formation and atherosclerosis

Macrophage foam cell formation, characterized by cholesterol ester accumulation catalyzed by acyl-CoA:cholesterol acyltransferase 1 (ACAT1), is the hallmark of early atherogenesis. We previously demonstrated the suppressive effects of incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), on the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE−/−) mice. The present study was performed to evaluate the suppressive effects of these incretins and GLP-1 analogs, such as exendin-4 and liraglutide, on human macrophage foam cell formation in vitro and those of liraglutide on atherosclerotic lesion development in apoE−/− mice. We investigated the suppressive effects of GLP-1, GIP, exendin-4, and liraglutide against oxidized low-density lipoprotein (oxLDL)-induced foam cell formation in primary cultured human monocyte-derived macrophages. Seventeen-week-old apoE−/− mice were administered a long-acting GLP-1 analog liraglutide by osmotic mini-pumps for 4 weeks. Aortic atherosclerosis, oxLDL-induced foam cell formation, and related gene expression in exudate peritoneal macrophages were determined in vivo and ex vivo. Receptors for GLP-1 and GIP were expressed at high levels in human aortic smooth muscle cells and monocytes, but at relatively low levels in human macrophages and foam cells. GLP-1, GIP, exendin-4, and liraglutide significantly suppressed oxLDL-induced foam cell formation mainly associated with ACAT1 down-regulation in human monocyte-derived macrophages. The infusion of liraglutide into apoE−/− mice significantly retarded atherosclerotic lesions with monocyte/macrophage infiltration in the aortic wall and suppressed foam cell formation and ACAT1 expression in macrophages. These findings indicate that liraglutide could prevent the development of atherosclerotic lesions by suppressing macrophage foam cell formation mainly associated with ACAT1 down-regulation.

Emerging Roles for Vasoactive Peptides in Diagnostic and Therapeutic Strategies Against Atherosclerotic Cardiovascular Diseases

Coronary artery disease (CAD) arising from atherosclerosis remains the most common cause of death and morbidity worldwide, although its risk factors, such as hypertension, dyslipidemia, and diabetes, have been individually treated with increasingly improved outcomes. Therefore, it is important to develop diagnostic and therapeutic windows for CAD. Many classical vasoactive hormones, inflammatory cytokines, and oxidative products have been implicated as potential biomarkers. Our recent studies have shown that high levels of the pro-atherogenic vasoactive agents, serotonin and urotensin II, which are potent vasoconstrictors, can be used as biomarkers for CAD. In subsequent trials, we unraveled anti- and pro-atherogenic roles for more recently identified peptides. Anti-atherogenic peptides include the adipocytokine adiponectin, the neuronal growth factor heregulin-β₁ (neuregulin-1 type I), the incretin hormone, glucagon-like peptide-1 (GLP-1), and a peptide recently identified by an in silico approach, salusin-α. Atherogenic roles have been demonstrated by cellular, animal, and clinical experiments, which indicate that human adiponectin, heregulin-β₁, GLP-1, and salusin-α attenuate the development of atherosclerotic lesions by suppressing macrophage foam cell formation via down-regulation of acyl-CoA:cholesterol acyltransferase-1. Circulating levels of these peptides in the blood are markedly decreased in CAD patients compared with those in non-CAD patients. Receiver operating characteristic curve analyses have shown that salusin-α is the most useful biomarker for detecting CAD among the four peptides examined. Therefore, salusin-α, alone or in various combinations with heregulin-β₁, adiponectin, and/or GLP-1, is a candidate biomarker for predicting CAD. Further, anti-atherogenic peptides could potentially serve as useful therapeutic targets for atherosclerotic cardiovascular diseases.

Endogenous Bioactive Peptides as Potential Biomarkers for Atherosclerotic Coronary Heart Disease

Cardiovascular disease is the leading cause of death worldwide, with high medical costs and rates of disability. It is therefore important to evaluate the use of cardiovascular biomarkers in the early diagnosis of coronary artery disease (CAD). We have screened a variety of recently identified bioactive peptides candidates in anticipation that they would allow detection of atherosclerotic CAD. Especially, we have focused on novel anti-atherogenic peptides as indicators and negative risk factors for CAD. In vitro, in vivo and clinical studies indicated that human adiponectin, heregulin-β1, glucagon-like peptide-1 (GLP-1), and salusin-α, peptides of 244, 71, 30, and 28 amino acids, respectively, attenuate the development and progression of atherosclerotic lesions by suppressing macrophage foam cell formation via down-regulation of acyl-coenzyme A: cholesterol acyltransferase-1. Circulating levels of these peptides in the blood are significantly decreased in patients with CAD compared to patients without CAD. Receiver operating characteristic analyses showed that salusin-α is a more useful biomarker, with better sensitivity and specificity, compared with the others for detecting CAD. Therefore, salusin-α, heregulin-β1, adiponectin, and/or GLP-1, alone or in various combinations, may be useful as biomarkers for atherosclerotic CAD.

Effects of PKF275-055, a dipeptidyl peptidase–4 inhibitor, on the development of atherosclerotic lesions in apolipoprotein E–null mice

We recently discovered that glucagon-like peptide–1 and glucose-dependent insulinotropic polypeptide can both prevent the development of atherosclerosis in apolipoprotein E–null (Apoe−/−) mice. In the present study, we attempted to extend these findings to orally administered dipeptidyl peptidase (DPP)–4 inhibitor. Seventeen-week-old Apoe−/− mice fed an atherogenic diet were administered a DPP-4 inhibitor, vildagliptin analogue (PKF275-055 [PKF], 100 µm/[kg d]), in drinking water over a period of 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein–induced foam cell formation were determined. Orally administered PKF increased plasma levels of active glucagon-like peptide–1 by 3.5-fold, increased total glucose-dependent insulinotropic polypeptide levels by 2-fold, reduced body weight by 13%, and reduced plasma cholesterol levels by 30%. Compared with drinking water controls, PKF significantly suppressed total aortic atherosclerotic lesions, atheromatous plaque in the aortic root, and macrophage accumulation in the aortic wall by 30% to 40% (P < .001). None of these changes were associated with the PKF-induced reductions in body weight and plasma cholesterol levels. Foam cell formation was suppressed by 40% in the exudate peritoneal macrophages obtained from the PKF-treated mice. The DPP-4 inhibitor prevents the development of atherosclerotic lesions by suppressing macrophage foam cell formation.

Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice

Aims/hypothesisSeveral lines of evidence suggest that incretin-based therapies suppress the development of cardiovascular disease in type 2 diabetes. We investigated the possibility that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can prevent the development of atherosclerosis in Apoe −/− mice.Methods Apoe −/− mice (17 weeks old) were administered GLP-1(7–36)amide, GLP-1(9–36)amide, GIP(1–42) or GIP(3–42) for 4 weeks. Aortic atherosclerosis, oxidised LDL-induced foam cell formation and related gene expression in exudate peritoneal macrophages were determined.ResultsAdministration of GLP-1(7–36)amide or GIP(1–42) significantly suppressed atherosclerotic lesions and macrophage infiltration in the aortic wall, compared with vehicle controls. These effects were cancelled by co-infusion with specific antagonists for GLP-1 and GIP receptors, namely exendin(9–39) or Pro3(GIP). The anti-atherosclerotic effects of GLP-1(7–36)amide and GIP(1–42) were associated with significant decreases in foam cell formation and downregulation of CD36 and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) in macrophages. GLP-1 and GIP receptors were both detected in Apoe −/− mouse macrophages. Ex vivo incubation of macrophages with GLP-1(7–36)amide or GIP(1–42) for 48 h significantly suppressed foam cell formation. This effect was wholly abolished in macrophages pretreated with exendin(9−39) or (Pro3)GIP, or with an adenylate cyclase inhibitor, MDL12,330A, and was mimicked by incubation with an adenylate cyclase activator, forskolin. The inactive forms, GLP-1(9–36)amide and GIP(3–42), had no effects on atherosclerosis and macrophage foam cell formation.Conclusions/interpretationOur study is the first to demonstrate that active forms of GLP-1 and GIP exert anti-atherogenic effects by suppressing macrophage foam cell formation via their own receptors, followed by cAMP activation. Molecular mechanisms underlying these effects are associated with the downregulation of CD36 and ACAT-1 by incretins.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2241-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Serum salusin-alpha level in rheumatoid arthritis

Rheumatoid arthritis (RA), a chronic inflammatory disease, leads to early and accelerated atherosclerosis; however, its pathogenesis is not yet fully documented. Salusin-α and β are novel bioactive peptides. Salusin-α suppresses macrophage foam cell formation, while salusin-β stimulates. Moreover, decreased serum salusin-α level has been reported previously in patients with coronary artery disease. The aims of the study were to assess serum salusin-α level and its association with predictors of atherosclerosis in a cohort of patients with RA.The study included 56 RA patients, 37 Behcet's disease (BD) patients, and 29 healthy controls (HC). TNF-α, IL-6 and salusin-α levels, homeostasis model assessment (HOMA-IR) index and common carotid intima-media thickness (IMT) were determined.In the RA and BD groups, salusin-α levels (p<0.001 and p<0.01, respectively) and IMTs (p<0.001 for both) were higher compared to the HC group. However, the level of salusin-α was not directly associated with the IMT in all the groups.Serum salusin-α levels are increased in RA and BD, although they have increased IMT. Salusin-α has been reported to have anti-atherogenic effects in previous studies. However, it seems that salusin-α does not directly affect the atherogenesis in RA and BD. Further studies are needed to understand the regulation of salusin-α and determination of its relations with the predictors of atherosclerosis in RA and BD.

Preventive Effects of Heregulin-β 1 on Macrophage Foam Cell Formation and Atherosclerosis

Rationale : Human heregulins, neuregulin-1 type I polypeptides that activate proliferation, differentiation, and survival of glial cells, neurons, and myocytes, are expressed in macrophage foam cells within human coronary atherosclerotic lesions. Macrophage foam cell formation, characterized by cholesterol ester accumulation, is modulated by scavenger receptor class A (SR-A), acyl-coenzyme A:cholesterol acyltransferase (ACAT)1, and ATP-binding cassette transporter (ABC)A1. Objective : The present study clarified the roles of heregulins in macrophage foam cell formation and atherosclerosis. Methods and Results : Plasma heregulin-β 1 levels were significantly decreased in 31 patients with acute coronary syndrome and 33 patients with effort angina pectoris compared with 34 patients with mild hypertension and 40 healthy volunteers (1.3±0.3, 2.0±0.4 versus 7.6±1.4, 8.2±1.2 ng/mL; P &lt;0.01). Among all patients with acute coronary syndrome and effort angina pectoris, plasma heregulin-β 1 levels were further decreased in accordance with the severity of coronary artery lesions. Expression of heregulin-β 1 was observed at trace levels in intracoronary atherothrombosis obtained by aspiration thrombectomy from acute coronary syndrome patients. Heregulin-β 1 , but not heregulin-α, significantly reduced acetylated low-density lipoprotein–induced cholesterol ester accumulation in primary cultured human monocyte-derived macrophages by reducing SR-A and ACAT1 expression and by increasing ABCA1 expression at both mRNA and protein levels. Heregulin-β 1 significantly decreased endocytic uptake of [ 125 I]acetylated low-density lipoprotein and ACAT activity, and increased cholesterol efflux to apolipoprotein (Apo)A-I from human macrophages. Chronic infusion of heregulin-β 1 into ApoE −/− mice significantly suppressed the development of atherosclerotic lesions. Conclusions : This study provided the first evidence that heregulin-β 1 inhibits atherogenesis and suppresses macrophage foam cell formation via SR-A and ACAT1 downregulation and ABCA1 upregulation.