The concept that atherosclerosis is an inflammation has been increasingly recognized, and subsequently resulted in great interest in revealing the inflammatory nature of the atherosclerotic process. More recently, a large body of evidence has supported the idea that inflammatory mechanisms play a pivotal role throughout all phases of atherogenesis, from endothelial dysfunction and the formation of fatty streaks to plaque destabilization and the acute coronary events due to vulnerable plaque rupture. Indeed, although triggers and pathways of inflammation are probably multiple and vary in different clinical entities of atherosclerotic disorders, an imbalance between anti-inflammatory mechanisms and pro-inflammatory factors will result in an atherosclerotic progression. Vascular endothelial dysfunction and lipoprotein retention into the arterial intima have been reported as the earliest events in atherogenesis with which inflammation is linked. Inflammatory has also been extended to the disorders of coronary microvasculature, and associated with special subsets of coronary artery disease such as silent myocardial ischemia, myocardial ischemia-reperfusion, cardiac syndrome X, variant angina, coronary artery ectasia, coronary calcification and in-stent restenosis. Inflammatory biomarkers, originally studied to better understand the pathophysiology of atherosclerosis, have generated increasing interest among researches and clinicians. The identification of inflammatory biomarkers and cellular/molecular pathways in atherosclerotic disease represent important goals in cardiovascular disease research, in particular with respect of the development of therapeutic strategies to prevent or reverse atherosclerotic diseases.
Atherosclerosis ; immunology ; metabolism ; Coronary Artery Disease ; immunology ; metabolism ; Humans ; Inflammation ; metabolism ; physiopathology

Atherosclerosis is an inflammatory disease as well as a lipid disorder. Atherosclerotic plaque formed in vessel walls may cause ischemia, and the rupture of vulnerable plaque may result in fatal events, like myocardial infarction or stroke. Because morphological imaging has limitations in diagnosing vulnerable plaque, molecular imaging has been developed, in particular, the use of nuclear imaging probes. Molecular imaging targets various aspects of vulnerable plaque, such as inflammatory cell accumulation, endothelial activation, proteolysis, neoangiogenesis, hypoxia, apoptosis, and calcification. Many preclinical and clinical studies have been conducted with various imaging probes and some of them have exhibited promising results. Despite some limitations in imaging technology, molecular imaging is expected to be used both in the research and clinical fields as imaging instruments become more advanced.
Atherosclerosis/*diagnosis/pathology/radiography ; Endothelial Cells/metabolism ; Humans ; Inflammation/pathology ; Lipoproteins, LDL/metabolism ; Macrophages/immunology/metabolism ; Plaque, Atherosclerotic ; Positron-Emission Tomography ; Tomography, Emission-Computed, Single-Photon

Atherosclerosis ; immunology ; metabolism ; pathology ; Biomarkers ; metabolism ; C-Reactive Protein ; metabolism ; Endothelium, Vascular ; metabolism ; pathology ; physiopathology ; Inflammation ; metabolism ; pathology ; Inflammation Mediators ; metabolism ; Interleukins ; metabolism ; Metabolic Syndrome ; metabolism ; pathology ; Tumor Necrosis Factor-alpha ; metabolism

Atherosclerosis is a chronic, inflammatory disorder characterized by the deposition of excess lipids in the arterial intima. The formation of macrophage-derived foam cells in a plaque is a hallmark of the development of atherosclerosis. Lipid homeostasis, especially cholesterol homeostasis, plays a crucial role during the formation of foam cells. Recently, lipid droplet-associated proteins, including PAT and CIDE family proteins, have been shown to control the development of atherosclerosis by regulating the formation, growth, stabilization and functions of lipid droplets in macrophage-derived foam cells. This review focuses on the potential mechanisms of formation of macrophage-derived foam cells in atherosclerosis with particular emphasis on the role of lipid homeostasis and lipid droplet-associated proteins. Understanding the process of foam cell formation will aid in the future discovery of novel therapeutic interventions for atherosclerosis.
Acyltransferases ; metabolism ; Apoptosis Regulatory Proteins ; metabolism ; Atherosclerosis ; metabolism ; pathology ; Cholesterol ; metabolism ; Foam Cells ; cytology ; metabolism ; Humans ; Lipid Metabolism ; physiology ; Macrophages ; cytology ; immunology ; Membrane Proteins ; metabolism ; Perilipin-2 ; Peroxisome Proliferator-Activated Receptors ; metabolism ; Sterol Regulatory Element Binding Proteins ; metabolism

Atherosclerosis is a chronic progressive inflammatory disorder and the leading cause of cardiovascular mortality. Here we assessed the dynamic changes of T-cell-derived cytokines, such as inteferon (IFN)-gamma, interleukin (IL)-17 and IL-4, during the progression of atherosclerosis in apolipoprotein E-null (ApoE(-/-)) mice, to understand the role of immune responses in different stages of atherosclerosis. Male ApoE(-/-) mice were fed a high-fat, western-type diet (WD: 21% lipid, 1.5% cholesterol) after 5 weeks of age and were compared with C57BL/6 wild-type control mice fed a standard chow diet. Atherosclerotic lesions appeared in the aortic sinus of ApoE(-/-) mice 4 weeks after WD and the lesions progressed and occupied >50% of the total sinus area 16 weeks after WD. Aortic IL-17 mRNA and protein expression started to increase in ApoE(-/-) mice after 4 weeks on the WD and peaked at around 8-12 weeks on the WD. In terms of systemic expression of T-cell-derived cytokines, IL-17 production from splenocytes after anti-CD3/CD28 stimuli increased from 4 weeks on the WD, peaked at 12 weeks and returned to control levels at 16 weeks. The production of IFN-gamma and IL-4 (Th1 and Th2 cytokines, respectively) from splenocytes was delayed compared with IL-17. Taken together, the present data indicate that Th17 cell response may be involved at an early stage in the development of atherosclerosis.
Animals ; Aorta/metabolism/*pathology ; Apolipoproteins E/*genetics ; Atherosclerosis/etiology/*genetics/immunology/*pathology ; Diet, High-Fat/adverse effects ; Gene Deletion ; Interferon-gamma/genetics ; Interleukin-17/*genetics/immunology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; T-Lymphocytes/immunology/metabolism/pathology ; Up-Regulation

Atherosclerosis is a chronic progressive inflammatory disorder and the leading cause of cardiovascular mortality. Here we assessed the dynamic changes of T-cell-derived cytokines, such as inteferon (IFN)-gamma, interleukin (IL)-17 and IL-4, during the progression of atherosclerosis in apolipoprotein E-null (ApoE(-/-)) mice, to understand the role of immune responses in different stages of atherosclerosis. Male ApoE(-/-) mice were fed a high-fat, western-type diet (WD: 21% lipid, 1.5% cholesterol) after 5 weeks of age and were compared with C57BL/6 wild-type control mice fed a standard chow diet. Atherosclerotic lesions appeared in the aortic sinus of ApoE(-/-) mice 4 weeks after WD and the lesions progressed and occupied >50% of the total sinus area 16 weeks after WD. Aortic IL-17 mRNA and protein expression started to increase in ApoE(-/-) mice after 4 weeks on the WD and peaked at around 8-12 weeks on the WD. In terms of systemic expression of T-cell-derived cytokines, IL-17 production from splenocytes after anti-CD3/CD28 stimuli increased from 4 weeks on the WD, peaked at 12 weeks and returned to control levels at 16 weeks. The production of IFN-gamma and IL-4 (Th1 and Th2 cytokines, respectively) from splenocytes was delayed compared with IL-17. Taken together, the present data indicate that Th17 cell response may be involved at an early stage in the development of atherosclerosis.
Animals ; Aorta/metabolism/*pathology ; Apolipoproteins E/*genetics ; Atherosclerosis/etiology/*genetics/immunology/*pathology ; Diet, High-Fat/adverse effects ; Gene Deletion ; Interferon-gamma/genetics ; Interleukin-17/*genetics/immunology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; T-Lymphocytes/immunology/metabolism/pathology ; Up-Regulation

OBJECTIVETo evaluate the effects of Chlamydia pneumoniae infection on oxidative stress and the development of atherosclerosis in C57BL/6J mice.

METHODSForty-eight C57BL/6J mice were divided into 4 groups including infection of CP and cholesterol diet, cholesterol diet, infection of CP and control. Atherosclerotic lesions were measured in the aortic root at 40 weeks after the primary infection. Production of superoxide was measured by lucigenin-enhanced chemiluminescence response and evaluated in situ with laser scanning confocal microscope.

RESULTSInfected mice fed with an atherogenic diet developed significantly larger lesion areas compared with the single atherogenic diet mice (135 249 +/- 43 748 microm2 vs. 96 378 +/- 30 945 microm2, P < 0.05). Superoxide generation was higher in aortic arches of the infected mice or atherogenic diet mice compared with the control mice (1974.25 +/- 650.49, 701.00 +/- 105.16, 455.62 +/- 77.54 counts.mg(-1).min(-1) vs. 142.25 +/- 31.82 counts.mg(-1).min(-1), respectively, P < 0.001).

CONCLUSIONChlamydia pneumoniae infection accelerates atherosclerotic lesion development in diet-induced hypercholesterolemic mice. Generation of reactive oxygen species may contribute to atherosclerotic development by Chlamydia pneumoniae infection.

Animals ; Antibodies, Bacterial ; blood ; Atherosclerosis ; etiology ; Chlamydia Infections ; complications ; metabolism ; Chlamydophila pneumoniae ; immunology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Superoxides ; metabolism

OBJECTIVE: To observe the effects of immune complexes (IC) prepared from human oxidized density lipoprotein (oxLDL) antibodies and human oxLDL on the foam cell forming and the macrophage activation, and to further uncover the possible mechanisms of immune complexes contributing to the atherosclerosis occurrence. METHODS: The immune complexes of human oxLDL and purified human oxLDL antibodies were added to culture U937 cells by protocols: polyethylene glycol-precipitated insoluble IC (PEG-IC) and IC immobilized by absorption to red blood cells (RBC-IC). With oxLDL as controls and heat-aggregated gamma globulin as an inhibitor of Fc gamma receptor, we measured the cholesterol ester, total cholesterol of the cellular extracts, and quantified the secreted MMP-1 of supernatants from U937 cells. RESULTS: A significant increase of MMP-1 release [(0.769 +/- 0.030) ng/ml vs (0.513 +/- 0.034) ng/ml, P < 0.01] and a higher level of cholesterol ester accumulation [(20.271 +/- 1.668) microg/mg protein vs (17. 226 +/- 1.298 ) microg/mg protein, P < 0.05] in U937 cells incubated with RBC-IC were observed, compared with those incubated with RBC-oxLDL. However, the above quantative difference between the cholesterol ester accumulation induced by oxLDL and insoluble PEG-IC was even more striking, and cholesterol ester accumulation was dosage-dependent. Heat-aggregated gamma globulin (10 mg/ml) as an inhibitor of Fc gamma receptors competitively inhibited cholesterol ester accumulation and decreased PEG-IC stimulating MMP-1 secretion to 71%. CONCLUSION Immune complexe of ox-LDL can transform macrophages into foam cells and activted macrophages. The immunological function of oxLDL is involved in the process of atherosclerosis occurrence.
Antibodies ; pharmacology ; Atherosclerosis ; etiology ; metabolism ; Cholesterol Esters ; metabolism ; Foam Cells ; drug effects ; Humans ; Lipoproteins, LDL ; immunology ; pharmacology ; Macrophage Activation ; drug effects ; Matrix Metalloproteinase 1 ; biosynthesis ; U937 Cells

OBJECTIVEA study was conducted to investigate the effects of Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) on the expression of regulated upon activation normal T-cell expressed and secreted (RANTES) and fractalkine in human umbilical vein endothelial cells (HUVECs).

METHODSHUVECs were incubated with different concentrations of Pg-LPS (200, 500, and 1000 ng x mL(-1)) for 1, 6, 12, and 24 h, respectively. Then real time quantitative polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent method (ELISA) were adopted to detect the protein levels and mRNA levels of RANTES and fractalkine.

RESULTSThe RANTES protein levels and mRNA levels, as well as fractalkine mRNA levels, were significantly higher in all experimental groups of 1, 6, and 12 h than in the control group (P<0.05), except the expression of RANTES mRNA in 200 ng x mL(-1) group of 12 h and RANTES protein in 200 ng x mL(-1) group of 1 h. The expression levels of RANTES mRNA and fractalkine mRNA were highest in 1000 ng x mL(-1) group of 6 h and were 4.88- and 6.20-fold higher, respectively, than those in the control group. The expression levels of RANTES protein, mRNA, and fractalkine mRNA decreased 6 h after stimulation, and were significantly higher than those in the control group (P<0.05) in the RANTES and fractalkine in HUVEC, and such expression is important in the development of atherosclerosis 500 ng x mL(-1) group of 24 h. There was a significant difference between the expression of fractalkine mRNA in 1000 ng x mL(-1) group of 6 and 12 h than in the control group (P<0.05).

CONCLUSIONPg-LPS infection might up-regulate the expression of RANTES and fractalkine in HUVEC, and such expression is important in the development of atherosclerosis.

Atherosclerosis ; Cells, Cultured ; Chemokine CCL5 ; genetics ; metabolism ; Chemokine CX3CL1 ; analysis ; genetics ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Human Umbilical Vein Endothelial Cells ; metabolism ; Humans ; Lipopolysaccharides ; pharmacology ; Porphyromonas gingivalis ; immunology ; isolation & purification ; RNA, Messenger ; analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Up-Regulation

It has been hypothesized that blood infusion of reconstituted HDL (rHDL) is a possible therapeutic strategy for the treatment of coronary artery disese. To compare short-term anti-inflammatory activity of wildtype (WT) apoA-I and point mutants, each rHDL containing WT, V156K, or R173C was infused into apo-E deficient atherosclerotic mice. Each rHDL was injected via the tail vein at a dosage of 120 mg/kg of body weight in 0.4 ml of tris-buffered saline (TBS), and blood was then collected at 24 and 48 h post-injection. Although regression activity was observed in each of the rHDL infused groups, a 30% reduction in the lipid-stained area of the aortic sinus was observed in the V156K and R173C-rHDL groups when compared to that of the WT-rHDL group, and this reduction was well correlated with an approximately 60% reduction in the accumulation of macrophages in the lesion area. Additionally, the groups that received the V156K and R173C-rHDL treatments showed smaller increases in the GOT, GPT, interleukin-6, myeloperoxidase (MPO) and lipid hydroperoxide (LPO) serum levels than those that received the WT-rHDL treatment. In addition, the strongest serum paraoxonase and ferric reducing ability was observed in the V156K and R173C-rHDL groups. In vitro nitration and chlorination of apoA-I by MPO treatment revealed that V156K-rHDL and R173C-rHDL were less susceptible to chlorination. Furthermore, rHDL treatment inhibited cellular uptake of oxidized LDL by macrophage cells and the production of proatherogenic species in culture media. In conclusion, blood infusions of the rHDLs exerted in vivo regression activity with anti-inflammatory and antioxidant activity in apo-E deficient mice and THP-1 cells, especially in those that were treated with V156K and R173C apoA-I.
Animals ; Anti-Inflammatory Agents/immunology/*therapeutic use ; Apolipoprotein A-I/blood/genetics/immunology/*therapeutic use ; Apolipoproteins E/genetics ; Aryldialkylphosphatase/blood/metabolism ; Atherosclerosis/*drug therapy ; Cell Line ; Cell Membrane Permeability ; Cholesterol/blood/metabolism ; Humans ; Lipoproteins, HDL/genetics/immunology/*therapeutic use ; Lipoproteins, LDL/metabolism ; Macrophages/cytology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidation-Reduction/*drug effects ; Peroxidase/blood/metabolism ; Point Mutation