Suppressed Foam Cell Formation Research Articles

Angptl 4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis

Angiopoietin-like protein family 4 (Angptl 4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). We generated ApoE −/−Angptl 4 −/− mice to study the effect of Angptl 4 deficiency on lipid metabolism and atherosclerosis. Fasting and postolive oil-loaded triglyceride (TG) levels were largely decreased in ApoE −/−Angptl 4 −/− mice compared with and ApoE −/−Angptl 4 +/+ mice. There was a significant (75 ± 12%) reduction in atherosclerotic lesion size in ApoE −/−Angptl 4 −/− mice compared with ApoE −/− Angptl 4 +/+ mice. Peritoneal macrophages, isolated from Angptl 4 −/− mice to investigate the foam cell formation, showed a significant decrease in newly synthesized cholesteryl ester (CE) accumulation induced by acetyl low-density lipoprotein (acLDL) compared with those from Angptl 4 +/+ mice. Thus, genetic knockout of Angptl 4 protects ApoE −/− mice against development and progression of atherosclerosis and strongly suppresses the ability of the macrophages to become foam cells in vitro.

Serum Salusin-.ALPHA. Levels Are Decreased and Correlated Negatively with Carotid Atherosclerosis in Essential Hypertensive Patients

Salusin-alpha is a new bioactive peptide with mild hypotensive and bradycardic effects. Our recent study showed that salusin-alpha suppresses foam cell formation in human monocyte-derived macrophages by down-regulating acyl-CoA:cholesterol acyltransferase-1, contributing to its anti-atherosclerotic effect. To clarify the clinical implications of salusin-alpha in hypertension and its complications, we examined the relationship between serum salusin-alpha levels and carotid atherosclerosis in hypertensive patients. The intima-media thickness (IMT) and plaque score in the carotid artery, blood pressure, serum levels of salusin-alpha, and atherosclerotic parameters were determined in 70 patients with essential hypertension and in 20 normotensive controls. There were no significant differences in age, gender, body mass index, fasting plasma glucose level, or serum levels of high-sensitive C-reactive protein, high- or low-density lipoprotein (LDL) cholesterol, small dense LDL, triglycerides, lipoprotein(a), or insulin between the two groups. Serum salusin-alpha levels were significantly lower in hypertensive patients than in normotensive controls. The plasma urotensin-II level, maximal IMT, plaque score, systolic and diastolic blood pressure, and homeostasis model assessment for insulin resistance (HOMA-IR) were significantly greater in hypertensive patients than in normotensive controls. In all subjects, maximal IMT was significantly correlated with age, systolic blood pressure, LDL cholesterol, urotensin-II, salusin-alpha, and HOMA-IR. Forward stepwise multiple linear regression analysis revealed that salusin-alpha levels had a significantly independent and negative association with maximal IMT. Serum salusin-alpha levels were significantly lower in accordance with the severity of plaque score. Our results suggest that the decrease in serum salusin-alpha, an anti-atherogenic peptide, may be associated with carotid atherosclerosis in hypertensive patients.

Requirement of JNK2 for Scavenger Receptor A-Mediated Foam Cell Formation in Atherogenesis

In vitro studies suggest a role for c-Jun N-terminal kinases (JNKs) in proatherogenic cellular processes. We show that atherosclerosis-prone ApoE-/- mice simultaneously lacking JNK2 (ApoE-/- JNK2-/- mice), but not ApoE-/- JNK1-/- mice, developed less atherosclerosis than do ApoE-/- mice. Pharmacological inhibition of JNK activity efficiently reduced plaque formation. Macrophages lacking JNK2 displayed suppressed foam cell formation caused by defective uptake and degradation of modified lipoproteins and showed increased amounts of the modified lipoprotein-binding and -internalizing scavenger receptor A (SR-A), whose phosphorylation was markedly decreased. Macrophage-restricted deletion of JNK2 was sufficient to decrease atherogenesis. Thus, JNK2-dependent phosphorylation of SR-A promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis.

Involvement of MCP-1 and M-CSF in glomerular foam cell formation in ExHC rats

An increase in glomerular macrophages (MO) is considered a potential effector mechanism by which hypercholesterolemia exacerbates glomerular injury. To investigate the mechanism underlying recruitment of MO into glomeruli, the expression of glomerular monocyte chemoattractant protein-1 (MCP-1) and macrophage colony-stimulating factor (M-CSF) mRNA were examined using a lipid-induced glomerular injury rat model. Eight-week-old male ExHC rats, a strain susceptible to hyperlipidemia, were divided into the following 4 groups: a control group (C), a high cholesterol diet group (HH), a high cholesterol diet/standard diet group (HN), which were fed a high cholesterol diet for the first 4 weeks and a standard diet for the following 4 weeks, and a probucol-treatment group (PT). Both MCP-1 and M-CSF mRNA expression in glomeruli were analyzed using the RT-PCR method. An additional experimental group (M) fed a high cholesterol diet was administered M-CSF daily for 4 weeks. The expression of MCP-1 mRNA in glomeruli increased accompanied by an increased total serum cholesterol level in HH and HN. However, M-CSF mRNA expression was significantly suppressed at 1 or 2 weeks and gradually increased to almost basal levels. In the PT group, MCP-1 mRNA expression was suppressed. The early suppression of M-CSF mRNA expression was inhibited in PT. Renal histology showed a significant increase in foam cells in glomeruli in HH and HN rats at 4 weeks. HH rats showed increased and expanded foam cells at 8 weeks. In HN rats, however, foam cells decreased significantly after the transfer to a standard diet from a high cholesterol diet. The MCP-1 mRNA expression was suppressed after the transfer. In the PT group, foam cell formation was also suppressed. Foam cells were identified as MO. M-CSF-treatment significantly suppressed foam cell formation in glomeruli when compared with the untreated group levels. These findings suggest that hypercholesterolemia stimulated the expression of MCP-1 in glomeruli and attracted the MO into glomeruli. They also suggest that the reduction of hypercholesterolemia after the change in diet or treatment with probucol suppressed glomerular injury by suppressing the glomerular MCP-1 expression. M-CSF may suppress the recruitment of MO into glomeruli and foam cell formation at an early stage of hypercholesterolemia-induced glomerular injury.

Effects of an HMG-CoA reductase inhibitor on cytokine production by human monocytes/macrophages.

It has been reported that the HMG-CoA reductase inhibitor simvastatin does not always effectively lower plasma LDL. This drug acts to monocytes/macrophages directly and inhibits cholesterol ester accumulation in these cells. However cytokine production in macrophages when simvastatin was administrated has not been described. In this study, we examined whether simvastatin affects cytokine production in human monocyte-derived macrophages. Simvastatin at doses ranging from 10(-9) to 10(-5) M did not affect the synthesis of proinflammatory cytokines (IL-1 beta, IL-6, IL-8) from human peripheral mononuclear cells. In addition, any changes in cytokine-induced cytokine production (IL-1-induced IL-8 synthesis) were not detected after the addition of simvastatin. The present results suggest that simvastatin suppresses foam cell formation in monocyte/macrophage, without affecting the immunological or inflammatory functions of these cells.

HMG-CoA還元酵素阻害剤(Simvastatin)のサイトカイン産生への影響について

It has been reported that although the HMG-CoA reductase inhibitor, simvastatin, does not always effectively lower plasma LDL, the drug inhibits LDL oxidation. Simvastatin may therefore prevent atherosclerosis by mechanisms other than its hypocholesterolemic activity. Foam cells in atherosclerotic lesions contain large amounts of cholesterol ester. The direct effects of simvastatin on cholesterol ester accumulation and cytokine production in macrophages have not been described. In this study, we determined whether simvastatin affects cholesterol ester accumulation and cytokine production by THP-1 cells and human peripheral mononuclear cells.Simvastatin decreased cholesterol ester accumulation without altering phospholipid accumulation in human monocyte THP-1 cells. However, free cholesterol and triglyceride levels rose slightly.In addition, the production of cytokines was measured in THP-1 cells and human peripheral mononuclear cells stimulated by simvastatin. Simvastatin at doses ranging from 10-9 to 10-5 M did not affect the synthesis of proinflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) from LPS-PMA-stimulated THP-1 cells. The synthesis of IL-1α, IL-1β, IL-6 and IL-8 from human peripheral mononuclear cells was also unaffected by administration of simvastatin. In addition, any changes in cytokineinduced cytokine production (IL-1-induced IL-8 synthesis) were not detected after the addition of simvastatin. The present results suggest that simvastatin suppresses foam cell formation in monocyte/macrophages, without affecting the immunological or inflammatory function of these cells.