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1.
Sci Rep ; 10(1): 6383, 2020 04 14.
Article in English | MEDLINE | ID: mdl-32286430

ABSTRACT

Periodontitis is a local and systemic inflammatory condition and a risk factor of atherosclerosis, but no studies investigated the effect of a statin on atherogenesis affected by severe periodontitis. In this study, we investigated the effect of rosuvastatin (RSV) on atherogenesis in Apolipoprotein E-deficient mice receiving silk ligature placement around the maxillary second molars. Mice with the ligature placement developed severe periodontitis and vascular inflammation. RSV significantly inhibited the development of periodontitis and vascular inflammation and remarkably blocked the increased lipid deposition and the atherogenic gene expression in the arterial wall and aortic sinus induced by severe periodontitis. To understand the mechanistic effect of RSV on periodontitis-associated atherogenesis, we investigated the in vitro effect of RSV on various effect of TNF-α, a major proinflammatory cytokine for periodontitis and atherogenesis. We found that RSV notably inhibited the TNF-α-induced osteoclast formation, endothelial cell phenotypic changes, foam cell formation, and the expression of CD47 and other oncogenes in arterial smooth muscle cells. Taken together, our study indicates that RSV prevents the exacerbation of atherosclerosis induced periodontitis by inhibiting local, systemic and vascular inflammation, as well as the expression of CD47 from arterial smooth muscle cells in mice.


Subject(s)
Atherosclerosis/drug therapy , Inflammation/drug therapy , Periodontitis/complications , Rosuvastatin Calcium/therapeutic use , Animals , Atherosclerosis/etiology , Cell Line , Cytokines/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Male , Mice , Mice, Knockout, ApoE , Osteoclasts/drug effects , Osteoclasts/pathology , Sinus of Valsalva/drug effects
2.
J Card Surg ; 34(6): 400-403, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30953447

ABSTRACT

OBJECTIVE: Sinus of Valsalva (SOV) aneurysms are rare and data on operative management are limited. They can cause right ventricular outflow tract or pulmonary artery compression, and rupture may be fatal. In this study, we describe our experience with the repair of 13 SOV aneurysms. METHODS: All patients who underwent SOV aneurysm repair from May 2001 to December 2017 at our single tertiary referral center were reviewed retrospectively. RESULTS: Thirteen patients (92% male) with a mean age of 60 years underwent repair of an SOV aneurysm; mean aneurysm diameter was 5.9 ± 0.8 cm and four patients (30.7%) presented with rupture into another cardiac chamber. Operative interventions included six Bentall procedures, five patch repairs (one with aortic valve replacement [AVR]), and two primary aneurysm closures both with concomitant AVR. There were no strokes, myocardial infarctions, re-explorations, or deaths in the postoperative period. After an average of 2.25 years, computed tomographic imaging in five patients demonstrated no aneurysm recurrence. CONCLUSIONS: Surgery is a safe option for both ruptured and nonruptured SOV aneurysms. A variety of repair strategies may be used. Larger studies are needed.


Subject(s)
Aortic Aneurysm/surgery , Aortic Rupture/surgery , Cardiac Surgical Procedures/methods , Sinus of Valsalva/surgery , Adult , Aortic Aneurysm/diagnostic imaging , Aortic Rupture/diagnostic imaging , Aortic Valve/surgery , Cardiac Valve Annuloplasty/methods , Female , Follow-Up Studies , Heart Valve Prosthesis Implantation/methods , Humans , Male , Middle Aged , Retrospective Studies , Sinus of Valsalva/drug effects , Time Factors , Tomography, X-Ray Computed , Treatment Outcome
3.
Am J Physiol Endocrinol Metab ; 316(5): E895-E907, 2019 05 01.
Article in English | MEDLINE | ID: mdl-30860874

ABSTRACT

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert potent glucose-lowering effects without increasing risks for hypoglycemia and weight gain. Preclinical studies have demonstrated direct antiatherogenic effects of GLP-1RAs in normoglycemic animal models; however, the underlying mechanisms in hyperglycemic conditions have not been fully clarified. Here we aimed to elucidate the role of AMP-activated protein kinase (AMPK) in antiatherogenic effects of GLP-1RAs in hyperglycemic mice. Streptozotocin-induced hyperglycemic apolipoprotein E-null mice were treated with vehicle, low-dose liraglutide (17 nmol·kg-1·day-1), or high-dose liraglutide (107 nmol·kg-1·day-1) in experiment 1 and the AMPK inhibitor dorsomorphin, dorsomorphin + low-dose liraglutide, or dorsomorphin + high-dose liraglutide in experiment 2. Four weeks after treatment, aortas were collected to assess atherosclerosis. In experiment 1, metabolic parameters were similar among the groups. Assessment of atherosclerosis revealed that high-dose liraglutide treatments reduced lipid deposition on the aortic surface and plaque volume and intraplaque macrophage accumulation at the aortic sinus. In experiment 2, liraglutide-induced AMPK phosphorylation in the aorta was abolished by dorsomorphin; however, the antiatherogenic effects of high-dose liraglutide were preserved. In cultured human umbilical vein endothelial cells, liraglutide suppressed tumor necrosis factor-induced expression of proatherogenic molecules; these effects were maintained under small interfering RNA-mediated knockdown of AMPKα1 and in the presence of dorsomorphin. Conversely, in human monocytic U937 cells, the anti-inflammatory effects of liraglutide were abolished by dorsomorphin. In conclusion, liraglutide exerted AMPK-independent antiatherogenic effects in hyperlipidemic mice with streptozotocin-induced hyperglycemia, with the possible involvement of AMPK-independent suppression of proatherogenic molecules in vascular endothelial cells.


Subject(s)
AMP-Activated Protein Kinases/genetics , Diabetes Mellitus, Experimental/metabolism , Hypoglycemic Agents/pharmacology , Liraglutide/pharmacology , Plaque, Atherosclerotic/pathology , Sinus of Valsalva/drug effects , AMP-Activated Protein Kinases/metabolism , Animals , Aorta/drug effects , Aorta/metabolism , Aorta/pathology , Atherosclerosis/metabolism , Atherosclerosis/pathology , Gene Knockdown Techniques , Hyperglycemia/metabolism , Macrophages , Mice , Mice, Knockout, ApoE , Plaque, Atherosclerotic/metabolism , Sinus of Valsalva/metabolism , Sinus of Valsalva/pathology
4.
Arterioscler Thromb Vasc Biol ; 38(1): 26-39, 2018 01.
Article in English | MEDLINE | ID: mdl-29162602

ABSTRACT

OBJECTIVE: Rosuvastatin has been widely used in the primary and secondary prevention of coronary heart disease. However, its antiatherosclerotic properties have not been tested in a mouse model that could mimic human coronary heart disease. The present study was designed to test the effects of rosuvastatin on coronary artery atherosclerosis and myocardial fibrosis in SR-B1 (scavenger receptor class B type 1) and apoE (apolipoprotein E) double knockout mice. APPROACH AND RESULTS: Three-week-old SR-B1-/-/apoE-/- mice were injected daily with 10 mg/kg of rosuvastatin for 2 weeks. Compared with saline-treated mice, rosuvastatin-treated mice showed increased levels of hepatic PCSK9 (proprotein convertase subtilisin/kexin type-9) and LDLR (low-density lipoprotein receptor) message, increased plasma PCSK9 protein but decreased levels of hepatic LDLR protein and increased plasma total cholesterol associated with apoB (apolipoprotein B) 48-containing lipoproteins. In spite of this, rosuvastatin treatment was associated with decreased atherosclerosis in both the aortic sinus and coronary arteries and reduced platelet accumulation in atherosclerotic coronary arteries. Cardiac fibrosis and cardiomegaly were also attenuated in rosuvastatin-treated SR-B1-/-/apoE-/- mice. Two-week treatment with rosuvastatin resulted in significant decreases in markers of oxidized phospholipids in atherosclerotic plaques. In vitro analysis showed that incubation of bone marrow-derived macrophages with rosuvastatin substantially downregulated cluster of differentiation (CD)36 and inhibited oxidized LDL-induced foam cell formation. CONCLUSIONS: Rosuvastatin protected SR-B1-/-/apoE-/- mice against atherosclerosis and platelet accumulation in coronary arteries and attenuated myocardial fibrosis and cardiomegaly, despite increased plasma total cholesterol. The ability of rosuvastatin to reduce oxidized phospholipids in atherosclerotic plaques and inhibit macrophage foam cell formation may have contributed to this protection.


Subject(s)
Aortic Diseases/prevention & control , Atherosclerosis/prevention & control , Cholesterol/blood , Coronary Artery Disease/prevention & control , Coronary Vessels/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Plaque, Atherosclerotic , Rosuvastatin Calcium/pharmacology , Scavenger Receptors, Class B/deficiency , Sinus of Valsalva/drug effects , Animals , Aortic Diseases/genetics , Aortic Diseases/metabolism , Aortic Diseases/pathology , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Biomarkers/blood , Cells, Cultured , Coronary Artery Disease/genetics , Coronary Artery Disease/metabolism , Coronary Artery Disease/pathology , Coronary Vessels/metabolism , Coronary Vessels/pathology , Disease Models, Animal , Foam Cells/drug effects , Foam Cells/metabolism , Foam Cells/pathology , Lipoproteins, LDL/metabolism , Liver/drug effects , Liver/metabolism , Mice, Knockout, ApoE , Proprotein Convertase 9/metabolism , Receptors, LDL/metabolism , Scavenger Receptors, Class B/genetics , Sinus of Valsalva/metabolism , Sinus of Valsalva/pathology
5.
J Cardiovasc Pharmacol ; 70(2): 110-118, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28763372

ABSTRACT

Di'ao Xinxuekang (XXK) is an herbal product in China and the Netherlands that has been clinically shown to attenuate atherosclerosis; however, the underlying antiatherosclerotic mechanism remains unclear. Because of its role in cholesterol homeostasis, reverse cholesterol transport (RCT) is a potential target for these beneficial effects. This study investigated the effects of XXK on RCT and related proteins. After treating ApoE-deficient mice with XXK for 8 weeks, we observed an increase in the expression level of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1, which in turn stimulated cholesterol efflux and reduced aortic atherosclerotic lesion area. XXK also increased high-density lipoprotein (HDL) synthesis by modulating the peroxisome proliferator-activated receptor γ/liver X receptor α/ATP-binding cassette transporter A1 pathway and promoted HDL maturity by increasing serum lecithin-cholesterol acyltransferase. In addition, XXK improved the selective uptake of HDL-cholesteryl ester by increasing the expression of scavenger receptor class B type I. This is the first study to show that XXK confers a regulation of RCT, at least in part, by improving HDL synthesis, maturation, and catabolism.


Subject(s)
Cholesterol/metabolism , Drugs, Chinese Herbal/pharmacology , Lipoproteins, HDL/biosynthesis , Animals , Biological Transport/drug effects , Biological Transport/physiology , Male , Metabolism/drug effects , Metabolism/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Sinus of Valsalva/drug effects , Sinus of Valsalva/metabolism
6.
Sci Rep ; 7(1): 3997, 2017 06 21.
Article in English | MEDLINE | ID: mdl-28638138

ABSTRACT

Atherosclerosis is the leading cause for cardiovascular mortality. We determined the effect of multi-antigenic construct expressing three peptides AHC (ApoB100, HSP60 and outer membrane protein of chlamydia pneumonia) in stabilizing advanced atherosclerosis in Apobtm2Sgy/Ldlrtm1Her/J mice. Atherosclerosis was induced by feeding high fat diet (HFD) to mice for 10 weeks, followed by five oral dosing with purified AHC or ovalbumin on alternate days and continued on HFD for another 10 weeks. Tolerance was associated with significantly higher numbers of regulatory T cells both in aortic sinus and spleen with higher mRNA expression of CTLA4 (3 fold), Foxp3 (1.4 folds) and TGF-ß (1.62) in aorta. Tregs cells were found to induce alternate activation of macrophages to M2 phenotype, with a reduction in plaque inflammation. AHC treatment showed evidence of plaque stabilization as observed by reduction in plaque necrosis in aortic sinus (35.8%) and in brachiocephalic artery (26%), with reduced expression of Tissue factor and MMP9. Macrophage apoptosis was reduced and collagen content was enhanced by treatment. Our results suggest that tolerance to atherogenic peptides increases regulatory T cells which activate M2 macrophages, prevent T cell proliferation and reduce plaque destabilization and inflammatory markers thus providing evidences for plaque stabilization in mice with advanced atherosclerosis.


Subject(s)
Apolipoprotein B-100/administration & dosage , Atherosclerosis/drug therapy , Bacterial Outer Membrane Proteins/administration & dosage , Chaperonin 60/administration & dosage , Peptides/administration & dosage , Animals , Aorta/drug effects , Aorta/physiopathology , Apolipoprotein B-100/genetics , Atherosclerosis/genetics , Atherosclerosis/immunology , Atherosclerosis/pathology , Bacterial Outer Membrane Proteins/chemistry , CTLA-4 Antigen/genetics , Cell Proliferation/drug effects , Chaperonin 60/genetics , Chlamydophila pneumoniae/chemistry , Diet, High-Fat/adverse effects , Forkhead Transcription Factors/genetics , Gene Expression Regulation/drug effects , Humans , Macrophages/drug effects , Macrophages/immunology , Matrix Metalloproteinase 9/genetics , Mice , Peptides/genetics , Sinus of Valsalva/drug effects , Sinus of Valsalva/immunology , Spleen/drug effects , Spleen/immunology , T-Lymphocytes, Regulatory/drug effects , Thromboplastin/genetics , Transforming Growth Factor beta/genetics
7.
Atherosclerosis ; 255: 156-163, 2016 12.
Article in English | MEDLINE | ID: mdl-27591127

ABSTRACT

BACKGROUND AND AIMS: Chinese dragon's blood has been used to treat blood stasis for thousands of years. Its total phenolic extract (Longxuetongluo capsule, LTC) is used for the treatment of ischemic stroke; however, its protective effect against atherosclerosis remains poorly understood. This paper aims to investigate the antiatherosclerotic effect of LTC and the underlying mechanisms in high-fat diet (HFD)-induced ApoE-/- mice. METHODS: The levels of plasma lipid and areas of atherosclerotic lesions in the aortic sinus in ApoE-/- mice were evaluated. The effect of LTC on the nitric oxide (NO) production in oxidized low-density lipoprotein (ox-LDL)-stimulated human umbilical vein endothelial cells (HUVECs) was determined. The adhesion of monocytes to ox-LDL-stimulated HUVECs was further studied. RESULTS: LTC at low, medium, and high doses markedly decreased the atherosclerotic lesion areas of the aortic sinus in HFD-induced ApoE-/- mice by 26.4% (p < 0.05), 30.1% (p < 0.05), and 46.5% (p < 0.01), respectively, although it did not improve the dyslipidemia. Furthermore, LTC restored the diminished NO production of ox-LDL-stimulated HUVECs (p < 0.001) and inhibited the adhesion between monocytes and endothelial cells (p < 0.01). LTC appeared to alleviate ox-LDL-stimulated dysfunction of HUVECs, and inhibit the adhesion of monocytes to HUVECs via the MAPK/IKK/IκB/NF-κB signaling pathway, thus decrease atherosclerotic lesions in the aortic sinus in HFD-induced ApoE-/- mice. CONCLUSIONS: These findings suggest the potential of LTC for use as an effective agent against atherosclerosis.


Subject(s)
Aortic Diseases/prevention & control , Apolipoproteins E/deficiency , Atherosclerosis/prevention & control , Diet, High-Fat , Drugs, Chinese Herbal/pharmacology , Endothelium, Vascular/drug effects , Sinus of Valsalva/drug effects , Animals , Aortic Diseases/genetics , Aortic Diseases/metabolism , Aortic Diseases/pathology , Apolipoproteins E/genetics , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cell Adhesion/drug effects , Cell Line, Transformed , Cell Line, Tumor , Coculture Techniques , Disease Models, Animal , Disease Progression , Dose-Response Relationship, Drug , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Genetic Predisposition to Disease , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Lipoproteins, LDL/pharmacology , Male , Mice, Knockout , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/metabolism , Phenotype , Plaque, Atherosclerotic , Signal Transduction/drug effects , Sinus of Valsalva/metabolism , Sinus of Valsalva/pathology , Time Factors
8.
Int J Mol Med ; 38(4): 1101-10, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27600281

ABSTRACT

Humulus japonicus (HJ) is used as a traditional medicine in Korea owing to its multiple properties including anti-mycobacterial, antioxidant and antihypertensive effects. The present study aimed to examine the anti­inflammatory and anti-atherogenic effects of a methanol extract of HJ. In lipopolysaccharide-stimulated RAW 264.7 cells, HJ significantly suppressed the mRNA expression and secretion of pro-inflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-1ß and IL-6)], and the release of inflammatory mediators such as nitrite and prostaglandin E2, together with a concomitant decrease in the mRNA levels of inducible nitric oxide synthase and cyclooxygenase-2. To examine whether HJ is capable of inhibiting experimental atherogenesis in an animal model, we randomly divided apolipoprotein E-deficient (apoE-/-) mice into three groups: mice fed an atherogenic diet plus vehicle (0.5% carboxymethyl cellulose) as the control vehicle group, and mice fed an atherogenic diet plus either 100 (HJ100) or 500 mg/kg (HJ500) of HJ as the experimental groups. After 12 weeks of HJ administration, lipid accumulation and the formation of atherosclerotic lesions in the aorta (en face) and the aortic sinus markedly decreased in the HJ500 group compared with the corresponding values in the vehicle control group. Moreover, monocyte and macrophage infiltration in the aortic sinus was markedly reduced in the HJ500 group. Reverse transcription-quantitative polymerase chain reaction analysis of the whole aorta showed that the mRNA levels of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, CD68 and IL-18 were significantly decreased in the HJ500 group. Collectively, these findings suggest that HJ may suppress atherosclerosis by inhibiting lipid accumulation and the expression of pro-atherogenic factors, and it may be effective at preventing the development of atherosclerosis.


Subject(s)
Apolipoproteins E/deficiency , Atherosclerosis/drug therapy , Humulus/chemistry , Plant Extracts/therapeutic use , Animals , Apolipoproteins E/metabolism , Atherosclerosis/blood , Atherosclerosis/genetics , Atherosclerosis/pathology , Cytokines/metabolism , Dinoprostone/biosynthesis , Gene Expression Regulation/drug effects , Inflammation/genetics , Inflammation/pathology , Inflammation Mediators/metabolism , Macrophages/drug effects , Macrophages/pathology , Male , Mice , Monocytes/drug effects , Monocytes/pathology , Nitrites/metabolism , Phytotherapy , Plant Extracts/pharmacology , RAW 264.7 Cells , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sinus of Valsalva/drug effects , Sinus of Valsalva/pathology
9.
Lipids ; 51(10): 1161-1170, 2016 10.
Article in English | MEDLINE | ID: mdl-27590239

ABSTRACT

Consumption of n-3 polyunsaturated fatty acids (PUFA) is associated with a reduced incidence of atherosclerosis. Perilla oil (PO) is a vegetable oil rich in α-linolenic acid (ALA), an n-3 PUFA. In this study, antiatherogenic effects and related mechanisms of PO were investigated in atherosclerotic mice. Apolipoprotein E knockout (ApoE KO) mice (male, n = 27) were fed high-cholesterol and high-fat diets containing 10 % w/w lard (LD), PO, or sunflower oil (SO) for 10 weeks. Plasma triglyceride, total cholesterol, and low-density lipoprotein cholesterol concentrations reduced in the PO and SO groups compared to the concentrations in the LD group (P < 0.05). The PO group showed reduced fatty streak lesion size at the aortic sinus (P < 0.05) compared to the sizes in the LD and SO groups. A morphometric analysis showed enhancement of endothelial nitric oxide synthase expression and reduction of inducible nitric oxide synthase expression in the PO group compared to that in the LD group (P < 0.05). Furthermore, aortic protein expression of intercellular cell adhesion molecule 1 and vascular cell adhesion molecule 1 was diminished in the PO group compared to that in the LD and SO groups (P < 0.05). These findings suggested that PO inhibited the development of aortic atherosclerosis by improving the plasma lipid profile, regulating nitric oxide synthase, and suppressing the vascular inflammatory response in the aorta of ApoE KO mice.


Subject(s)
Apolipoproteins E/genetics , Atherosclerosis/drug therapy , Lipids/blood , Nitric Oxide Synthase/metabolism , alpha-Linolenic Acid/administration & dosage , Animals , Atherosclerosis/chemically induced , Atherosclerosis/metabolism , Diet, High-Fat/adverse effects , Disease Models, Animal , Gene Expression Regulation/drug effects , Male , Mice , Mice, Knockout , Plant Oils/administration & dosage , Plant Oils/pharmacology , Random Allocation , Sinus of Valsalva/drug effects , alpha-Linolenic Acid/pharmacology
10.
Am J Physiol Endocrinol Metab ; 311(2): E335-45, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27221119

ABSTRACT

It has been argued whether insulin accelerates or prevents atherosclerosis. Although results from in vitro studies have been conflicting, recent in vivo mice studies demonstrated antiatherogenic effects of insulin. Insulin is a known activator of endothelial nitric oxide synthase (NOS), leading to increased production of NO, which has potent antiatherogenic effects. We aimed to examine the role of NOS in the protective effects of insulin against atherosclerosis. Male apolipoprotein E-null mice (8 wk old) fed a high-cholesterol diet (1.25% cholesterol) were assigned to the following 12-wk treatments: control, insulin (0.05 U/day via subcutaneous pellet), N(ω)-nitro-l-arginine methyl ester hydrochloride (l-NAME, via drinking water at 100 mg/l), and insulin plus l-NAME. Insulin reduced atherosclerotic plaque burden in the descending aorta by 42% compared with control (plaque area/aorta lumen area: control, 16.5 ± 1.9%; insulin, 9.6 ± 1.3%, P < 0.05). Although insulin did not decrease plaque burden in the aortic sinus, macrophage accumulation in the plaque was decreased by insulin. Furthermore, insulin increased smooth muscle actin and collagen content and decreased plaque necrosis, consistent with increased plaque stability. In addition, insulin treatment increased plasma NO levels, decreased inducible NOS staining, and tended to increase phosphorylated vasodilator-stimulated phosphoprotein staining in the plaques of the aortic sinus. All these effects of insulin were abolished by coadministration of l-NAME, whereas l-NAME alone showed no effect. Insulin also tended to increase phosphorylated endothelial NOS and total neuronal NOS staining, effects not modified by l-NAME. In conclusion, we demonstrate that insulin treatment decreases atherosclerotic plaque burden and increases plaque stability through NOS-dependent mechanisms.


Subject(s)
Aorta/drug effects , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Insulin/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/drug effects , Plaque, Atherosclerotic/metabolism , Actins/drug effects , Actins/metabolism , Animals , Aorta/metabolism , Aorta/pathology , Apolipoproteins E/genetics , Collagen/drug effects , Collagen/metabolism , Macrophages/drug effects , Macrophages/pathology , Male , Mice , Mice, Knockout , Necrosis , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type I/drug effects , Nitric Oxide Synthase Type I/metabolism , Nitric Oxide Synthase Type III/drug effects , Nitric Oxide Synthase Type III/metabolism , Phosphoproteins/drug effects , Phosphoproteins/metabolism , Plaque, Atherosclerotic/pathology , Sinus of Valsalva/drug effects , Sinus of Valsalva/metabolism , Sinus of Valsalva/pathology
11.
Horm Metab Res ; 48(3): 196-200, 2016 Mar.
Article in English | MEDLINE | ID: mdl-25951321

ABSTRACT

Klotho is a transmembrane protein, expressed mainly in the kidneys and the choroid plexus. The extracellular domain of klotho is composed of 2 internal repeats, KL1 and KL2, which can be cleaved and act as hormones. Klotho-deficient mice develop a phenotype resembling human aging. Laboratory and clinical data suggest a favorable effect of klotho on atherosclerosis, high blood pressure, and metabolic syndrome. Therefore, we aimed to study the effect of klotho treatment on atherogenesis, blood pressure, and metabolic parameters in experimental rodent models. Fructose-fed Sprague-Dawley rats (metabolic syndrome model) and apolipoprotein E (apoE -/-) knock-out mice (atherosclerosis model) were treated with either klotho or its active domain KL1. In apoE -/- mice, klotho unexpectedly elevated plasma cholesterol and triglyceride levels compared to the control group. Yet, it did not increase the aortic sinus atherosclerotic lesion area. In fructose-fed Sprague-Dawley rats, klotho treatment did not lower blood pressure or plasma triglyceride levels. Although KL1 treatment did not lower blood pressure or plasma insulin levels, it significantly reduced the elevation of total plasma triglyceride levels (from 2.3-fold to 1.6-fold, p<0.05) due to lower triglyceride-rich VLDL levels. Klotho did not show any beneficial effects on atherosclerosis and components of the metabolic syndrome and was associated with increased plasma cholesterol levels. On the other hand, treatment with KL1 may lower plasma triglyceride levels independent of insulin. Additional studies are required in order to decipher the complex role of klotho and its active domains in the regulation of plasma lipid levels.


Subject(s)
Atherosclerosis/drug therapy , Atherosclerosis/physiopathology , Blood Pressure/drug effects , Glucuronidase/therapeutic use , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/metabolism , Atherosclerosis/complications , Diet , Disease Models, Animal , Glucuronidase/chemistry , Glucuronidase/pharmacology , Humans , Klotho Proteins , Lipid Metabolism/drug effects , Male , Metabolic Syndrome/complications , Metabolic Syndrome/drug therapy , Mice, Inbred C57BL , Protein Domains , Rats, Sprague-Dawley , Sinus of Valsalva/drug effects , Sinus of Valsalva/pathology , Triglycerides/metabolism
12.
PLoS One ; 10(5): e0125126, 2015.
Article in English | MEDLINE | ID: mdl-25938460

ABSTRACT

There is strong epidemiological association between periodontal disease and cardiovascular disease but underlying mechanisms remain ill-defined. Because the human periodontal disease pathogen, Porphyromonas gingivalis (Pg), interacts with innate immune receptors Toll-like Receptor (TLR) 2 and CD36/scavenger receptor-B2 (SR-B2), we studied how CD36/SR-B2 and TLR pathways promote Pg-mediated atherosclerosis. Western diet fed low density lipoprotein receptor knockout (Ldlr°) mice infected orally with Pg had a significant increase in lesion burden compared with uninfected controls.This increase was entirely CD36/SR-B2-dependent, as there was no significant change in lesion burden between infected and uninfected Cd36o/Ldlro mice [corrected]. Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1ß generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure. CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1ß generation, but also resulted in LPS induced lethality (pyroptosis). Modified forms of LDL inhibited Pg-mediated IL1ß generation in a CD36/SR-B2-dependent manner and prevented pyroptosis, but promoted foam cell formation. Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1ß release. In the vessel wall, macrophages encountering systemic release of IL1ß, PgLPS and modified LDL have increased lipid uptake, foam cell formation, and release of IL1ß, but because pyroptosis is inhibited, this enables macrophage survival and promotes increased plaque development. These studies may explain increased lesion burden as a result of periodontal disease, and suggest strategies for development of therapeutics.


Subject(s)
Atherosclerosis/complications , Atherosclerosis/microbiology , CD36 Antigens/metabolism , Porphyromonas gingivalis/physiology , Receptors, LDL/deficiency , Toll-Like Receptor 2/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Apoptosis/drug effects , Atherosclerosis/blood , Bacteroidaceae Infections/blood , Bacteroidaceae Infections/complications , Bacteroidaceae Infections/metabolism , Bacteroidaceae Infections/pathology , Body Weight/drug effects , Carrier Proteins/metabolism , Disease Models, Animal , Feeding Behavior , Female , Foam Cells/metabolism , Inflammasomes/metabolism , Interferon-gamma/blood , Interleukin-1beta/metabolism , Interleukin-6/blood , Lipopolysaccharides/pharmacology , Lipoproteins, LDL/pharmacology , Male , Mice, Inbred C57BL , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein , Porphyromonas gingivalis/drug effects , Receptors, LDL/metabolism , Risk Factors , Sinus of Valsalva/drug effects , Sinus of Valsalva/microbiology , Sinus of Valsalva/pathology
13.
J Cardiovasc Pharmacol ; 64(4): 318-25, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24853487

ABSTRACT

OBJECTIVES: The CC chemokine ligand-20 (CCL-20)/macrophage inflammatory protein-3α has been seen as one of the most important chemokines and played a key role in atherogenesis, but the mechanism that underlies the regulation of CCL-20 has not been established clearly yet. The aim of this study was to investigate the influence of salvianolic acid A (SAA) on the expression of CCL-20 in macrophages and ApoE-deficient (ApoE) mice. METHODS: The expression of CCL-20 was detected both at protein and messenger RNA levels in RAW264.7 cells. We validated the result in ApoE mice that were intraperitoneally injected with SAA. Phosphorylation of p38 mitogen-activated protein kinase was detected with Western blot, and inhibitor of p38 was used to investigate the mechanism of regulation of CCL-20. Hematoxylin and eosin and Oil-Red-O staining were used to evaluate the atherosclerotic lesions and lipid accumulation in ApoE mice. Immunohistochemical analysis was used to detect the expressions of CCL-20 and CCR6 in the atherosclerotic lesions. Immunofluorescent analysis was used to certify the origination of CCL-20. RESULTS: Recombinant tumor necrosis factor-α (TNF-α) upregulated CCL-20 production in dose- and time-dependent manners in RAW264.7 cells. The activity of TNF-α-induced CCL-20 production seemed to be significantly suppressed by SAA. Using p38 mitogen-activated protein kinase inhibitor, we found that p38 mediated the effects of TNF-α- and SAA-induced CCL-20 expression changes. In addition, immunohistochemical analysis of aortic root of ApoE mice also demonstrated that the expressions of CCL-20 and CCR6 were both downregulated significantly with SAA treatment. Furthermore, treatment of SAA inhibited the progression of the atherosclerotic plaques and lipid accumulation. CONCLUSIONS: These results demonstrate that TNF-α increased but SAA suppressed CCL-20 production significantly via a novel mechanism.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Atherosclerosis/drug therapy , Caffeic Acids/pharmacology , Chemokine CCL20/genetics , Lactates/pharmacology , Macrophages/drug effects , Tumor Necrosis Factor-alpha/pharmacology , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Blotting, Western , Cell Line , Chemokine CCL20/immunology , Disease Models, Animal , Dose-Response Relationship, Drug , Lipid Metabolism/drug effects , Macrophages/immunology , Mice, Inbred C57BL , Mice, Knockout , Real-Time Polymerase Chain Reaction , Recombinant Proteins , Sinus of Valsalva/drug effects , Sinus of Valsalva/metabolism , Sinus of Valsalva/pathology , Time Factors , Tumor Necrosis Factor-alpha/immunology , Up-Regulation
14.
J Physiol Sci ; 64(4): 291-303, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24817684

ABSTRACT

Our laboratory has demonstrated that the cardiomotor component of aortic baroreflex is temporarily inhibited at the onset of spontaneous motor activity in decerebrate cats, without altering carotid sinus baroreflex. A reason for this dissociation may be attributed to a difference in the responses between aortic nerve activity (AoNA) and carotid sinus nerve activity (CsNA) during spontaneous motor activity. The stimulus-response curves of AoNA and CsNA against mean arterial blood pressure (MAP) were compared between the pressor interventions evoked by spontaneous motor activity and by intravenous administration of phenylephrine or norepinephrine, in which the responses in heart rate (HR) were opposite (i.e., tachycardia vs. baroreflex bradycardia), despite the identical increase in MAP of 34-40 mmHg. In parallel to the pressor response, mean AoNA and CsNA increased similarly by 78-81 and by 88 % of the baseline control, respectively, irrespective of whether the pressor response was evoked by spontaneous motor activity or by a pharmacological intervention. The slope of the stimulus-response curve of the mean AoNA became greater (P < 0.05) during spontaneous motor activity as compared to the pharmacological intervention. On the other hand, the stimulus-response curve of the mean CsNA and its slope were equal (P > 0.05) between the two pressor interventions. Furthermore, the slopes of the stimulus-response curves of both diastolic AoNA and CsNA (defined as the minimal value within a beat) exhibited a greater increase during spontaneous motor activity. All differences in the slopes of the stimulus-response curves were abolished by restraining HR at the intrinsic cardiac frequency. In conclusion, mean mass activities of both aortic and carotid sinus baroreceptors are able to encode the beat-by-beat changes in MAP not only at rest but also during spontaneous motor activity and spontaneous motor activity-related reduction of aortic baroreceptor activity is denied accordingly.


Subject(s)
Carotid Sinus/drug effects , Carotid Sinus/physiology , Motor Activity/physiology , Pressoreceptors/metabolism , Sinus of Valsalva/drug effects , Sinus of Valsalva/physiology , Vasoconstrictor Agents/pharmacology , Animals , Baroreflex/drug effects , Baroreflex/physiology , Blood Pressure/drug effects , Blood Pressure/physiology , Carotid Sinus/metabolism , Cats , Heart/drug effects , Heart Rate/drug effects , Heart Rate/physiology , Motor Activity/drug effects , Norepinephrine/pharmacology , Phenylephrine/pharmacology , Sinus of Valsalva/metabolism
16.
PLoS One ; 9(3): e92095, 2014.
Article in English | MEDLINE | ID: mdl-24647529

ABSTRACT

BACKGROUND: The lipid milleu exacerbates the inflammatory response in atherosclerosis but its effect on T cell mediated immune response has not been fully elucidated. We hypothesized that lipid lowering would modulate T cell mediated immune function. METHODS AND RESULTS: T cells isolated from human PBMC or splenic T cells from apoE-/- mouse had higher proliferative response to T cell receptor (TCR) ligation in medium supplemented with 10% fetal bovine serum (FBS) compared to medium with 10% delipidated FBS. The differences in proliferation were associated with changes in lipid rafts, cellular cholesterol content, IL-10 secretion and subsequent activation of signaling molecule activated by TCR ligation. Immune biomarkers were also assessed in vivo using male apoE-/- mice fed atherogenic diet (AD) starting at 7 weeks of age. At 25 weeks of age, a sub-group was switched to normal diet (ND) whereas the rest remained on AD until euthanasia at 29 weeks of age. Dietary change resulted in a lower circulating level of cholesterol, reduced plaque size and inflammatory phenotype of plaques. These changes were associated with reduced intracellular IL-10 and IL-12 expression in CD4+ and CD8+ T cells. CONCLUSION: Our results show that lipid lowering reduces T cell proliferation and function, supporting the notion that lipid lowering modulates T cell function in vivo and in vitro.


Subject(s)
Cholesterol/metabolism , T-Lymphocytes/immunology , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/metabolism , Blotting, Western , Cell Proliferation/drug effects , Cell Separation , Cholesterol/blood , Culture Media/pharmacology , Dietary Fats/pharmacology , Enzyme-Linked Immunosorbent Assay , Esterification , Humans , Interleukin-10/metabolism , Lymphocyte Activation/drug effects , Male , Membrane Microdomains/drug effects , Membrane Microdomains/metabolism , Mice, Inbred C57BL , Phosphorylation/drug effects , Plaque, Atherosclerotic/pathology , Sinus of Valsalva/drug effects , Sinus of Valsalva/metabolism , Sinus of Valsalva/pathology , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , ZAP-70 Protein-Tyrosine Kinase/metabolism
17.
PLoS One ; 9(2): e88767, 2014.
Article in English | MEDLINE | ID: mdl-24586387

ABSTRACT

BACKGROUND: Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice. METHODS: Mice were fed atherogenic diets with normal vitamin D content (1.5 IU/kg) or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography. RESULTS: Vitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001), trabecular bone volume (p<0.01) and bone mineral density (p<0.005). These changes were accompanied by an increase in calcification density (number of calcifications per mm(2)) of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01). Paricalcitol administration suppressed parathyroid hormone (p<0.001), elevated plasma calcium phosphate product (p<0.005) and induced an increase in calcification density (472 versus 200, p<0.005) similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions. CONCLUSION: Vitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal range of vitamin D signalling may be important for prevention of atherosclerotic calcification.


Subject(s)
Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Calcinosis/complications , Plaque, Atherosclerotic/complications , Plaque, Atherosclerotic/metabolism , Vitamin D Deficiency/complications , Vitamin D/pharmacology , Animals , Diet , Ergocalciferols/pharmacology , Hypertrophy, Left Ventricular/complications , Male , Mice , Mice, Knockout , Sinus of Valsalva/drug effects
18.
PLoS One ; 6(10): e25541, 2011.
Article in English | MEDLINE | ID: mdl-22003398

ABSTRACT

AIM: 15-deoxy-Δ¹²,¹4 prostaglandin J2 (15d-PGJ2) is a ligand of peroxisome proliferator-activated receptor γ (PPARγ) having diverse effects such as the differentiation of adipocytes and atherosclerotic lesion formation. 15d-PGJ2 can also regulate the expression of inflammatory mediators on immune cells independent of PPARγ. We investigated the antiatherogenic effect of 15d-PGJ2. METHODS: We fed apolipoprotein (apo) E-deficient female mice a Western-type diet from 8 to 16 wk of age and administered 1 mg/kg/day 15d-PGJ2 intraperitoneally. We measured atherosclerotic lesions at the aortic root, and examined the expression of macrophage and inflammatory atherosclerotic molecules by immunohistochemical and real-time PCR in the lesion. RESULTS: Atherosclerotic lesion formation was reduced in apo E-null mice treated with 15d-PGJ2, as compared to in the controls. Immunohistochemical and real-time PCR analyses showed that the expression of MCP-1, TNF-α, and MMP-9 in atherosclerotic lesions was significantly decreased in 15d-PGJ2 treated mice. The 15d-PGJ2 also reduced the expression of macrophages and RelA mRNA in atherosclerotic lesions. CONCLUSION: This is the first report 15d-PGJ2, a natural PPARγ agonist, can improve atherosclerotic lesions in vivo. 15d-PGJ2 may be a beneficial therapeutic agent for atherosclerosis.


Subject(s)
Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Gene Knockout Techniques , Plaque, Atherosclerotic/drug therapy , Plaque, Atherosclerotic/genetics , Prostaglandin D2/analogs & derivatives , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/metabolism , Aorta, Thoracic/pathology , Body Weight/drug effects , Female , Gene Expression Regulation/drug effects , Lipids/blood , Mice , Mice, Inbred C57BL , Mice, Knockout , Plaque, Atherosclerotic/blood , Plaque, Atherosclerotic/physiopathology , Prostaglandin D2/pharmacology , Prostaglandin D2/therapeutic use , Sinus of Valsalva/drug effects , Sinus of Valsalva/metabolism , Sinus of Valsalva/pathology
19.
PLoS One ; 6(8): e23425, 2011.
Article in English | MEDLINE | ID: mdl-21909350

ABSTRACT

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is thought to play modulatory roles in the development of atherosclerosis. Here we evaluated the effects of a specific lp-PLA2 inhibitor on atherosclerosis in ApoE-deficient mice and its associated mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: ApoE-deficient mice fed an atherogenic high-fat diet for 17 weeks were divided into two groups. One group was administered the specific lp-PLA2 inhibitor, darapladib (50 mg/kg/day; p.o.) daily for 6 weeks, while the control group was administered saline. We observed no differences in body weight and serum lipids levels between the two groups at the end of the dietary period. Notably, serum lp-PLA2 activity as well as hs-CRP (C-reactive protein) and IL-6 (Interleukin-6) levels were significantly reduced in the darapladib group, compared with the vehicle group, while the serum PAF (platelet-activating factor) levels were similar between the two groups. Furthermore, the plaque area through the arch to the abdominal aorta was reduced in the darapladib group. Another finding of interest was that the macrophage content was decreased while collagen content was increased in atherosclerotic lesions at the aortic sinus in the darapladib group, compared with the vehicle group. Finally, quantitative RT-PCR performed to determine the expression patterns of specific inflammatory genes at atherosclerotic aortas revealed lower expression of MCP-1, VCAM-1 and TNF-α in the darapladib group. CONCLUSIONS/SIGNIFICANCE: Inhibition of lp-PLA2 by darapladib leads to attenuation of in vivo inflammation and decreased plaque formation in ApoE-deficient mice, supporting an anti-atherogenic role during the progression of atherosclerosis.


Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/antagonists & inhibitors , 1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism , Apolipoproteins E/deficiency , Inflammation/complications , Inflammation/enzymology , Plaque, Atherosclerotic/complications , Plaque, Atherosclerotic/enzymology , 1-Alkyl-2-acetylglycerophosphocholine Esterase/blood , Animals , Apolipoproteins E/metabolism , Benzaldehydes/pharmacology , Biomarkers/blood , C-Reactive Protein/metabolism , Gene Expression Regulation/drug effects , Humans , Inflammation/blood , Inflammation/genetics , Inflammation Mediators/blood , Lipids/blood , Mice , Mice, Inbred C57BL , Oximes/pharmacology , Plaque, Atherosclerotic/blood , Plaque, Atherosclerotic/pathology , Sinus of Valsalva/drug effects , Sinus of Valsalva/pathology
20.
Microvasc Res ; 77(3): 364-9, 2009 May.
Article in English | MEDLINE | ID: mdl-19323972

ABSTRACT

AIM: Clopidogrel is a widely used anti-thrombotic for the prevention of stent thrombosis and cardiovascular events in patients with coronary atherosclerosis. Clopidogrel has been shown to exhibit anti-inflammatory effects that are related to the attenuated activation of platelets. Atherosclerosis is a complex process in which the immune system and the endothelium appear to play a prominent role. Herein, we tested the hypothesis that clopidogrel will influence plaque size and composition in the atherosclerosis prone apolipoprotein E knockout (apoE KO) mouse model. METHODS AND RESULTS: Eight week old mice were fed daily with either PBS, 1 mg or 2 mg of clopidogrel for 10 weeks. Plaque size was evaluated in the aortic sinus and cellular and humoral responses were studied as well as splenic and bone marrow endothelial progenitors by FACS. Treatment with either 1 mg and 2 mg of clopidogrel significantly reduced plaque size and augmented its stability by increasing atheromatous fibrous area. Whereas antigen specific oxLDL immune response was not influenced by clopidogrel feeding, the number of atheroprotective regulatory CD4+CD25+ T cells was significantly increased. Moreover, clopidogrel treatment resulted in a prominent rise in splenic but not bone marrow derived Sca-1+/flk-1+ endothelial progenitors. CONCLUSION: Clopidogrel significantly reduces atheroma burden and stabilizes aortic sinus plaques in apoE KO mice. These effects may partially be mediated by upregulation of the regulatory T cell pool and splenic endothelial progenitor cells. These findings may expand the potential applications of clopidogrel in human subjects.


Subject(s)
Apolipoproteins E , Atherosclerosis/drug therapy , Platelet Aggregation Inhibitors/pharmacology , Sinus of Valsalva/drug effects , Ticlopidine/analogs & derivatives , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Atherosclerosis/pathology , Cell Proliferation/drug effects , Cells, Cultured , Clopidogrel , Disease Models, Animal , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Female , Fibrosis/chemically induced , Fibrosis/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Sinus of Valsalva/pathology , Spleen/cytology , Spleen/drug effects , Stem Cells/cytology , Stem Cells/drug effects , T-Lymphocytes, Regulatory/pathology , Ticlopidine/pharmacology
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