Anti-atherosclerosis Research Articles

The effect of dual antioxidant modification on oxidative stress resistance and anti-dysfunction of non-split HDL and recombinant HDL

Recombinant high-density lipoprotein (rHDL) as anti-atherosclerosis (AS) vehicle has unique advantages including multiple anti-atherogenic functions and homing features to plaques. However, rHDL may be converted into dysfunctional forms due to complex treatment during preparation. Herein, oxidation-induced dysfunction of non-split HDL and rHDL was initially investigated. It was found that although both non-split HDL and rHDL showed oxidative dysfunction behavior, non-split HDL demonstrated superior oxidation defense compared to rHDL due to its intact composition and avoidance of overprocessing such as split and recombination. Unfortunately, in vivo oxidative stress could compromise the functionality of HDL. Therefore, surface engineering of non-split HDL and rHDL with cascade antioxidant enzyme analogues Ebselen and mitochondrial-targeted TPGS-Tempo was conducted to construct a dual-line defense HDL nano system (i.e., T@E-HDLs/rHDL), aiming to restore plaque redox balance and preserving the physiological function of HDL. Results indicated that both T@E-HDLs and rHDLs performed without distinction and exhibited greater resistance to oxidative stress damage as well as better functions than unmodified HDLs in macrophage foam cells. Overall, the modification of dual antioxidants strategy bridges the gap between non-split HDL and rHDL, and provides a promising resolution for the dilemmas of oxidative stress in plaques and HDL self dysfunction.

The Key Role of Liraglutide in Preventing Autophagy of Vascular Smooth Muscle Cells in High Glucose Conditions

The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (LIRA) is a potential hypoglycemic drug with anti-atherosclerosis (AS) effects. Autophagy in the vascular smooth muscle cells (VSMCs) facilitates AS. However, the role of autophagy in the anti-AS mechanism of LIRA remains unclear. To examine the role and mechanisms of autophagy in LIRA’s improvement of the biological characteristics of VSMCs in high glucose conditions. Experimental animal study. VSMCs isolated from the thoracic aorta of male SD rats were subjected to a high glucose (HG) condition (25 mM) in Dulbecco’s Modified Eagle’s Medium with or without LIRA, the GLP-1 receptor antagonist exendin9-39 (Exe9-39), a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), and autophagy inhibitors (3-methyladenine [3-MA] and bafilomycin A1 [Baf A1]). Acridine orange staining, western blotting, transmission electron microscopy, and mCherry-GFP-LC3 transfection were performed to evaluate the autophagy flux. Additionally, VSMC migration, calcification, proliferation, and apoptosis in HG conditions were observed. Addition of LIRA alone or in combination with autophagy inhibitors significantly downregulated Beclin, increased the LC3-II/LC3-I ratio, and upregulated p62 in VSMCs in HG conditions. Furthermore, autophagolysosome formation was markedly curbed after treatment with LIRA and/or autophagy inhibitors. Inhibition of autophagy by LIRA and/or the autophagy inhibitors attenuated VSMC phenotype conversion, proliferation, migration, and calcification and promoted VSMC apoptosis in HG conditions. This protective role of LIRA was augmented by LY294002, but inhibited by Exe9-39. LIRA plays a significant role in the improvement of the biological features of VSMCs in HG conditions.

Impact of Some Antioxidants (Allicin-AL, Saponin -SN, Carotenes-CN, Euginol, Vitamins C and E) Rich Vegetables on Common Metabolic Lipid Parameters

Attempt at comparing the impact of some antioxidant – rich vegetables (singularly or combinations) on common atherosclerosis lipid parameters. The experiments were conducted in three phases. Phase (A) Five (5) ml each of aqueous extract of (i) fresh (ocimum gratissimum) scent leaf (ii) bitter leafs (vernonia amygdalina) (iii) 2.5ml each of bitter leaf and scent leaf mix; was mixed thoroughly with 100g of normal rat feed. Phase (B) five (5) ml each of aqueous extract of (i) utazi (gongronema latifolium) leafs (ii) aloevera leafs (iii) 2.5g each of utazi and aloe vera mix; was mixed into 100g normal rat feed. The third phase involved 5g each of (i) fresh (docasus carota) carrot (ii) tomato (solanum lycopersicum) (iii) carrot and tomato mix. Each of the nine (9) feed samples (3 from each phase) were separately feed to a set of three albino rats for 21 days; so was 100% (control) rat feed and garlic supplemented (5g crushed garlic, blended with 100g) rat feed. The weights, feed intake and weight of droppings of the rats were recorded at three days’ intervals during experimental feeding. The blood samples of the rats were harvested at the end of the 21 days and lipid analysis carried out on them. The rat feeds supplemented with utazi, nchanwu and aloevera leafs’ water extracts respectively scored 2.7, 3.7 and 2.9mmol/ml respectively regarding total cholesterol; all significantly lower than the normal range of 5.17mmol/ml (p ≤ 0.05). With respect to triglycerides, 1.9, 1.9 and 1.7 respectively scored by Utazi, aloe vera and bitter leaf supplemented feeds were all close to the acceptable range of 0.7 – 1.7Mmol/ml. The combined effect of utazi and Aloe vera on HDL, was significantly lowering (0.5Mmol/ml) compared to 1.5 and 1.6 Mmol/ml of individual Utazi and Aloe vera respectively. The three feed samples (Utazi/aleovera, tomatoe/carrot and bitter leaf/scent leaf) that combined two vegetables rich in same or different antioxidants, all reported lower weight gains with collaborating lower scores in lipid parameters; clue for broad spectrum anti atherosclerosis therapy preparation.

Papain exerts an anti-atherosclerosis effect with suppressed MPA-mediated foam cell formation by regulating the MAPK and PI3K/Akt-NF-κB pathways

ABSTRACT Background Papain possesses a potential anti-atherosclerosis (AS) effect. This study aimed to explore the inhibitory effects of papain on the monocyte-platelet aggregates (MPAs)-mediated production of foam cells in vitro and AS in vivo. Research design and methods THP-1 cells were treated by platelet, papain, nuclear factor-κB (NF-κB) inhibitor or activator. An AS rat model was treated with papain. The THP-1 cells, macrophages, and foam cells were detected, and CD36, CD11b and CCR2 (macrophages) and CD14 and CD41 (MPAs) were measured. The levels of inflammatory factors, lipoprotein, and MAPK and PI3K/Akt -NF-κB pathways proteins were determined. Finally, injury of the thoracic aorta of AS rats was observed. Results Papain reduced macrophage production, lipid accumulation, and foam cell formation in vitro and downregulated the expression of monocyte chemoattractant protein 1 (MCP-1), prostaglandin E2 (PGE2), and cyclooxygenase 2 (COX2), and that of p38, JNK, Akt, and p65. Moreover, NF-κB activator could reversed the inhibitory effects of papain. Similarly, papain alleviated aortic smooth muscle hyperplasia, lipid droplet accumulation, and collagen diffusion and inhibited the expression of inflammatory factors and p38, JNK, Akt, and p65 in vivo. Conclusions Papain inhibited MPA-induced foam cell formation by inactivating the MAPK and PI3K/Akt-NF-κB pathways, thereby exerting an anti-AS effect.

Usnea improves high-fat diet- and vitamin D3-induced atherosclerosis in rats by remodeling intestinal flora homeostasis.

Background: Usnea has various pharmacological properties, including anti-inflammatory, antitumor, antioxidant, antiviral, and cardiovasculoprotective effects. Aim of the study: To investigate the potential mechanisms underlying the anti-atherosclerosis (AS) activity of Usnea ethanol extract (UEE) via the regulation of intestinal flora. Materials and Methods: The chemical composition of UEE was determined using ultra-performance liquid chromatography with quadrupole exactive orbitrap mass spectrometry (UPLC-Q-EOMS). Thirty-six male Sprague-Dawley rats were divided into six groups. A high-fat diet and intraperitoneal vitamin D3 injections were used to establish a rat model of AS. After 4weeks of treatment with UEE, hematoxylin-eosin staining was performed to evaluate the pathomorphology of the aorta, liver, and colon. The composition and diversity of the rat intestinal flora were determined using high-throughput 16S rRNA sequencing. Enzyme-linked immunosorbent assays were used to measure the levels of plasma trimethylamine oxide (TMAO), serum bile acid (BA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). The protein expression of cholesterol 7α-hydroxylase (CYP7A1) and flavin monooxygenase 3 (FMO3) in the liver and zonula occludens-1 (ZO-1) and occludin in colon tissue was detected via western blotting. Results: Forty-four compounds were identified in UEE. In the rat model of AS, UEE significantly prevented calcium deposition; decreased the serum levels of TC, TG, LDL-C, LPS, TNF-α, and IL-6; and increased the serum level of HDL-C. Additionally, all UEE dosages decreased the relative abundance of Verrucomicrobiota while increased that of Bacteroidetes. FMO3 protein expression and TMAO levels decreased, whereas CYP7A1 protein expression and BA levels increased. The absorption of intestinal-derived LPS was minimized. Furthermore, the protein expression of ZO-1 and occludin was upregulated. Conclusion: UEE ameliorated AS. The underlying mechanism was the reversal of imbalances in the intestinal flora by Usnea, thereby inhibiting calcium deposition, abnormal lipid metabolism, and inflammatory response.

Peptide-Based HDL as an Effective Delivery System for Lipophilic Drugs to Restrain Atherosclerosis Development.

PurposePeptide-based high-density lipoprotein (pHDL) structurally and functionally resembles the natural HDL as anti-atherosclerosis (AS) therapies. Since pHDL contains a large hydrophobic core, this study aims to evaluate the potentials of pHDL as a hydrophobic drug carrier and the efficiency of drug-loaded pHDL in the control of AS.MethodsThe pHDL encapsulation of hydrophobic components from natural plants, including curcumin (Cur) and tanshinone IIA (TanIIA), was achieved using one-step microfluidics. Then, morphological features and loading efficiencies of pHDL-Cur and pHDL-TanIIA were determined by TEM and high-performance liquid chromatography (HPLC), respectively. Taking the fluorescence advantage of Cur, localizations of loaded Cur in pHDL were investigated by fluorescence quenchers, and recruitments of Cur to AS plaques were assessed with ex vivo imaging. Based on anti-inflammatory properties of TanIIA, pHDL-TanIIA was accordingly developed to evaluate the anti-AS effects through examinations of plasma lipid parameters and pathological alterations of plaque-associated regions.ResultsBoth lipophilic Cur and TanIIA can be efficiently loaded into pHDL carriers. The resultant pHDL-Cur and pHDL-TanIIA inherit the homogeneous nano-disk structure of pHDL. By using pHDL-Cur, the encapsulated hydrophobics are tracked in the core of pHDL, and incorporations of Cur with pHDL vehicles greatly improve the bioavailability and association of Cur with AS plaques. Moreover, when loaded with TanIIA, which has established its role in anti-AS as an anti-inflammatory candidate, synergistic effects in reducing AS lesions and improving pathological alterations of main organs related to AS were achieved.ConclusionThe pHDL system could potentially be applied for both imaging and therapy in animal models of AS. Benefits of pHDL-based drug delivery will potentially extend the application scenarios of bioactive chemicals from natural plants which are underutilized due to features like low bioavailability and facilitate the clinical translation of synthetic HDL therapies in HDL-associated disorders, including but not limited to AS.

BIOLOGICALLY ACTIVE SUBSTANCES OF ALLIUM GENUS AND THEIR PHAR-MACOLOGICAL ACTION

Intensive Chemical and pharmacological investiagtion of species Allium is conducted by Italien, French, English,American, Indian, Chinese and Japonaise scientists during the last years. The medicinal drugs with anticancer, antimicrobal, anti  atherosclerosis activity. Taking into account the above mentioned, it is perspective to continue the study of species Allium grown in Georgia to receive the medicinal drugs with high therapeutic effect.

Network Pharmacology-Based Strategy Combined with Molecular Docking and in vitro Validation Study to Explore the Underlying Mechanism of Huo Luo Xiao Ling Dan in Treating Atherosclerosis.

BackgroundHuo Luo Xiao Ling Dan (HLXLD), a famous Traditional Chinese Medicine (TCM) classical formula, possesses anti-atherosclerosis (AS) activity. However, the underlying molecular mechanisms remain obscure.AimThe network pharmacology approach, molecular docking strategy, and in vitro validation experiment were performed to explore the potential active compounds, key targets, main signaling pathways, and underlying molecular mechanisms of HLXLD in treating AS.MethodsSeveral public databases were used to search for active components and targets of HLXLD, as well as AS-related targets. Crucial bioactive ingredients, potential targets, and signaling pathways were acquired through bioinformatics analysis. Subsequently, the molecular docking strategy and molecular dynamics simulation were carried out to predict the affinity and stability of active compounds and key targets. In vitro cell experiment was performed to verify the findings from bioinformatics analysis.ResultsA total of 108 candidate compounds and 321 predicted target genes were screened. Bioinformatics analysis suggested that quercetin, dihydrotanshinone I, pelargonidin, luteolin, guggulsterone, and β-sitosterol may be the main ingredients. STAT3, HSP90AA1, TP53, and AKT1 could be the key targets. MAPK signaling pathway might play an important role in HLXLD against AS. Molecular docking and molecular dynamics simulation results suggested that the active compounds bound well and stably to their targets. Cell experiments showed that the intracellular accumulation of lipid and increased secretory of TNF-α, IL-1β, and MCP-1 in ox-LDL treated RAW264.7 cells, which can be significantly suppressed by pretreating with dihydrotanshinone I. The up-regulation of STAT3, ERK, JNK, and p38 phosphorylation induced by ox-LDL can be inhibited by pretreating with dihydrotanshinone I.ConclusionOur findings comprehensively demonstrated the active compounds, key targets, main signaling pathways, and underlying molecular mechanisms of HLXLD in treating AS. These findings would provide a scientific basis for the study of the complex mechanisms underlying disease and drug action.

Paeonol Attenuated Vascular Fibrosis Through Regulating Treg/Th17 Balance in a Gut Microbiota-Dependent Manner.

Background: Paeonol (Pae) is a natural phenolic compound isolated from Cortex Moutan, which exhibits anti-atherosclerosis (AS) effects. Our previous work demonstrated that gut microbiota plays an important role during AS treatment as it affects the efficacy of Pae. However, the mechanism of Pae in protecting against vascular fibrosis as related to gut microbiota has yet to be elucidated. Objective: To investigate the antifibrosis effect of Pae on AS mice and demonstrate the underlying gut microbiota-dependent mechanism. Methods: ApoE-/- mice were fed with high-fat diet (HFD) to replicate the AS model. H&E and Masson staining were used to observe the plaque formation and collagen deposition. Short-chain fatty acid (SCFA) production was analyzed through LC-MS/MS. The frequency of immune cells in spleen was phenotyped by flow cytometry. The mRNA expression of aortic inflammatory cytokines was detected by qRT-PCR. The protein expression of LOX and fibrosis-related indicators were examined by western blot. Results: Pae restricted the development of AS and collagen deposition. Notably, the antifibrosis effect of Pae was achieved by regulating the gut microbiota. LC-MS/MS data indicated that the level of SCFAs was increased in caecum contents. Additionally, Pae administration selectively upregulated the frequency of regulatory T (Treg) cells as well as downregulated the ratio of T helper type 17 (Th17) cells in the spleen of AS mice, improving the Treg/Th17 balance. In addition, as expected, Pae intervention can significantly downregulate the levels of proinflammatory cytokines IL-1β, IL-6, TNF-α, and IL-17 in the aorta, and upregulate the levels of anti-inflammatory factor IL-10, a marker of Treg cells. Finally, Pae’s intervention in the gut microbiota resulted in the restoration of the balance of Treg/Th17, which indirectly downregulated the protein expression level of LOX and fibrosis-related indicators (MMP-2/9 and collagen I/III). Conclusion: Pae attenuated vascular fibrosis in a gut microbiota-dependent manner. The underlying protective mechanism was associated with the improved Treg/Th17 balance in spleen mediated through the increased microbiota-derived SCFA production. Collectively, our results demonstrated the role of Pae as a potential gut microbiota modulator to prevent and treat AS.

Combined NOX/ROS/PKC Signaling Pathway and Metabolomic Analysis Reveals the Mechanism of TRAM34-Induced Endothelial Progenitor Cell Senescence.

It has been shown that the KCa3.1 channel-specific blocker, TRAM34, is a promising antiatherosclerosis (AS) agent, but its side effects restrict its clinical application. Notably, its effect on endothelial progenitor cells (EPCs) is unclear. We aim to unravel the effect of TRAM34 on EPCs and identify the underlying mechanism. Rats were injected intraperitoneally with TRAM34, and EPCs were isolated from bone marrow. The gene and protein levels of corresponding factors were detected by real-time PCR, enzyme-linked immunosorbent assay, western blotting, and fluorescence-activated cell sorting. Liquid chromatography-tandem mass spectrometry (LC-MS) was applied to detect metabolite differences. We showed that when rats were treated with TRAM34 in vivo, colony formation and proliferation of early EPCs were reduced, but their senescence and apoptosis were enhanced. Moreover, TRAM34 enhanced NOX activity, promoted an increase in intracellular ROS levels, increased PKC expression, and subsequently promoted EPC senescence, which is unfavorable for EPC angiogenesis in vivo and in vitro. Combining these results with LC-MS data, we found that TRAM34 significantly promoted pyrimidine and purine metabolism, leading to cellular senescence. Furthermore, the NOX inhibitor, Setanaxib, enhanced antioxidant metabolic pathways, especially S-adenosylmethioninamine (SAM) metabolism, to exert an antisenescence effect. Finally, we confirmed that SAM alleviates TRAM34-induced cellular senescence, suggesting an efficient approach to improve the quality of endogenous EPCs. This study reveals the mechanism of TRAM34-induced EPC senescence, providing a solution for the extended application of KCa3.1 inhibitor in AS.

Juice from Fructus Rosae Roxburghii normalizes blood lipids in mice with diet-induced hyperlipidemia*†.

Fructus Rosae Roxburghii (FRR) as a dietary supplement is considered to possess anti‐atherosclerosis (AS), and hyperlipidemia (HLP) is material basis for AS formation, so the effects and molecular mechanism of FRR on diet‐induced hyperlipidemic mice were explored. In Diet IV2 group, hepatic steatosis was significantly relieved; meanwhile, TC, TG, LDL‐C, HDL‐C, and ASI in serum were regulated to control level. Thirty‐seven DCEG in Diet I, Diet II, and Diet IV2 groups were obtained by RNA‐seq analysis. Relative mRNA levels were further determined by qRT‐PCR, of which 28 genes were matched with those detected by RNA‐seq. Ten DCEP were verified by targeted quantitative proteomic analysis, but expressive patterns of only six proteins were correlated with qRT‐PCR data. These DCEG and DCEP played important roles in regulating the biosynthesis of BAs and steroids, fatty acid metabolism, and LPO production. They might cooperatively regulate the function of HDL or RCT by PPAR signaling pathway under the FRR action. As we know, it is the first time the potential anti‐atherosclerotic mechanism of FRR regulating the blood lipids was explored.

Ziziphora clinopodioides flavonoids based on network pharmacology attenuates atherosclerosis in rats induced by high-fat emulsion combined with vitamin D3 by down-regulating VEGF/AKT/NF-κB signaling pathway

Ziziphora clinopodioides flavonoids (ZCF) is a major bioactive total flavonoids compound isolated from Ziziphora clinopodioides Lam. It has been long used as an anti-atherosclerosis (AS) in clinics. However, anti-AS effects of ZCF have not been fully investigated. The objective of this study is to further investigate the anti-AS activities and mechanisms of ZCF in vivo. The main chemical components, action targets and signal pathways of Ziziphora clinopodioides Lam were predicted and analyzed by network pharmacology technology. The main bioactive components of Ziziphora clinopodioides Lam were identified using high performance liquid chromatography-mass spectrometry (HPLC-MS). In vivo experiments, atherosclerosis in rats induced by high-fat emulsion combined with vitamin D3 and treated with simvastatin (0.45 mg/kg/d), ZCF (6.25, 12.5, 25 g/kg/d) for 7 weeks.We found that ZCF significantly reduced blood lipid levels (TG, TC, and LDL-C), and decreased lipid deposition in the aorta and atherosclerotic lesion size, inhibited mitochondrial mem- brane potential (MMP2/9/12/13) impairment. Meanwhile, ZCF may down-regulated the levels of VEGF, AKT, NF-κB, ICAM-1 and VCAM-1 proteins, indicating ZCF may play an anti-atherosclerotic role by down-regulating the VEGF/AKT/NF-κB signaling pathway.Results from this study demonstrated that ZCF have an anti-AS ability to lower lipid concentrations and protect endothelial function, antioxidant and anti-inflammatory activity, and suggested that ZCF might be a potential therapeutic drug in the prevention of AS.

Ticagrelor suppresses oxidized low‑density lipoprotein‑induced endothelial cell apoptosis and alleviates atherosclerosis in ApoE‑/‑ mice via downregulation of PCSK9.

Although ticagrelor has been demonstrated to possess an anti-atherosclerosis (AS) effect, its underlying mechanism remains unclear. In the present study, it was investigated whether ticagrelor reduces oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell apoptosis, an initial step for the development of AS, and alleviates AS in apolipoprotein-E-deficient (ApoE−/−) mice by inhibiting the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9). The human endothelial cell line EAhy926 was treated with ox-LDL, ox-LDL + ticagrelor (40 µmol/l) and ox-LDL + ticagrelor (60 µmol/l) for 24 h. Cell apoptosis was detected using Annexin V-fluorescein isothiocyanate/propidium iodide staining. The expression levels of PCSK9, apoptosis-associated proteins and signaling pathways were determined by reverse transcription-quantitative polymerase chain reaction and western blotting. ApoE−/− mice fed a high-fat diet were used to induce an AS model. After 20 weeks, ApoE−/− mice were randomly assigned to receive saline or ticagrelor intragastrically for 10 days. The formation of atherosclerotic plaques was detected by hematoxylin and eosin staining. The expression of PCSK9 in the arterial tissues was measured by immunohistochemistry. The results demonstrated that treatment with ticagrelor was able to decrease ox-LDL-induced apoptosis in a concentration-dependent manner (40 µmol/l vs. ox-LDL, 17.58±2.66 vs. 27.25±5.54%; 60 µmol/l vs. ox-LDL, 12.26±1.54 vs. 27.25±5.54%). The mRNA and protein expression level of PCSK9 significantly decreased following treatment with ticagrelor, accompanied with upregulation of B-cell lymphoma (Bcl) 2 and downregulation of Bcl-2 associated X, apoptosis regulator, caspase-3, p38, phosphorylated-(p) p38, p-c-Jun N-terminal kinases (JNK), p-extracellular signal-regulated kinases and the ratio of p-JNK to JNK. Histological analysis of arterial tissues revealed ticagrelor markedly decreased the atherosclerotic plaque area and inhibited the expression of PCSK9. The present results suggested that ticagrelor may alleviate AS via downregulation of PCSK9-mediated endothelial cell apoptosis, which may be JNK-dependent.

Effects of Gualou Xiebai Banxia decoction on blood lipid content, oxidative stress and ox-LDL/Lox-1 pathway in ApoE-/- mice

To observe the functions of Gualou Xiebai Banxia decoction（GXBD） on regulating lipid metabolism, anti-oxidation, and interposing ox-LDL/Lox-1 pathway, and to explore its anti-atherosclerosis (AS) mechanisms. AS models were established by using 42 Apo-E-/- male mice with high fat diet. AS model mice were randomly divided into the model group, simvastatin group, and GXBD high and low dose groups. C57BL/6J male mice were used as the normal control group, n=10 and the treatment lasted for 8 weeks. The levels of TC, TG, LDL-C, HDL-C, SOD, MDA, GSH-px, and ox-LDL in blood serum were tested 24 h after the last administration. The changes of aortic tissues structure were observed by HE staining; the expression levels of Lox-1 protein and the expression levels of mRNA were detected by Western blot and PCR respectively.Results showed that the blood lipid levels and MDA, ox-LDL levels in blood serum of model group were significantly higher than those in the normal control group, but SOD, GSH-px levels were significantly lower than those in the normal control group, and the Lox-1 protein and mRNA expression levels were also significantly higher than those in the control group(P<0.05), namely aortic atherosclerosis lesions were obvious in model group.The levels of blood lipid and MDA, ox-LDL of GXBD high and low dose groups and simvastatin group were significantly lower than those in model group, while SOD, GSH-px levels were significantly higher than those in model group, and Lox-1 protein and mRNA expression levels were significantly lower than those in model group(P<0.05), namely the aortic atherosclerosis lesions were significantly relieved. The above results indicated that GXBD was capable of modulating blood lipid, anti-oxidation, and inhibiting the expression of Lox-1, and interposing ox-LDL/Lox-1 pathway in the AS model Apo-E-/- mice, which may be one of the mechanisms of anti-atherosclerosis.

The Value and Distribution of High-Density Lipoprotein Subclass in Patients with Acute Coronary Syndrome

BackgroundHigh-density lipoprotein (HDL) enhances cholesterol efflux from the arterial wall and exhibits potent anti-inflammatory and anti-atherosclerosis (AS) properties. Whether raised HDL levels will clinically benefit patients with acute coronary syndrome (ACS) and the value at which these effects will be apparent, however, is debatable. This study examined the HDL subclass distribution profile in patients with ACS.MethodsPlasma HDL subclasses were measured in 158 patients with established ACS and quantified by two-dimensional gel electrophoresis and immunoblotting. ACS diagnosis was based on symptoms of cardiac ischemia, electrocardiogram (ECG) abnormalities, speciality cardiac enzyme change along with presence of coronary heart disease (CHD) on coronary angiography.ResultsThe small-sized preβ1-HDL, HDL3b, and HDL3a levels were significantly higher, and the large-sized HDL2a and HDL2b levels were significantly lower in patients with ACS than in those with stable angina pectoris (SAP) and in normal control subjects. Meanwhile, with an elevation in the low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), body mass index (BMI), and blood pressure (BP), and the reduction in the high density lipoprotein cholesterol (HDL-C) levels, the HDL2b contents significantly decreased and the preβ1-HDL contents significantly increased in patients with ACS. The correlation analysis revealed that the apolipoprotein (apo)A-I levels were positively and significantly with all HDL subclasses contents; plasma total cholesterol (TC) and fasting plasma glucose (FPG) levels were inversely associated with HDL2a, and HDL2b. Moreover, the FPG levels were positively related to HDL3c, HDL3b, and HDL3a in ACS patients.ConclusionThe HDL subclass distribution profile remodeling was noted in the patients with ACS. Plasma lipoprotein and FPG levels, BP, and BMI play an important role in the HDL subclass metabolism disorder for patients with ACS. The HDL subclass distribution phenotype might be useful as a novel biomarker to assist in the risk stratification of patients with ACS.

ASSA13-03-49 The Compare Study of the Protective Effects of Resveratrol and Atorvastatin to Oxidative Sresss on Human Umbilical Vein Endothelial Cells

<h3>Background and Objective</h3> Oxidative stress plays an important role in atherosclerosis and endothelial cell is one of the initiating place of atherosclerosis. The oxidative-stress-induced endothelial dysfunction is the key pathway of atherosclerosis. NO, MDA, LDH, SOD are peroxidative products of lipid derived catalyzation. They are useful indexes of in vivo lipid peroxidation. Statins are anti—atherosclerosis drugs which widely are used in clinic practise. Previous studies indicated that the athero-protective effect may be related to the anti-oxidative effect. Resteratrol is a well-known anti-oxidative drug produced by a restricted number of plant species. The differences in anti-oxidative capabilities of statins and resveratrol may reflect their differences in anti-atherosclerosis activities. This study is aiming to assess the anti-oxidative effects of statins and resveratrol by inhibiting production of NO, MDA, LDH and SOD in peroxide hydrogen stimulated human umbilical vein endothelial cell (HUVEC). <h3>Methods</h3> HUVEC were co-incubated in the same medium in presence of different concentrations of atorvastatin (1μmol/l) and resveratrol (1μmol/l, 5μmol/l, 10μmol/l) for 24 hours and also 48 hours, and in peroxide hydrogen (10 μmol/l) for 2 hours. After stimulation, the supernatants were collected to measure NO, MDA, LDH and SOD using enzyme-linked immunosorbent assays (ELISA). And the survival rates of HUVEC were detected by MTT assay. <h3>Results</h3> Peroxide hydrogen at dose of l0μmol/l can induce enhanced oxidant stress in HUVECs. The values of MTT were significantly reduced, the content of NO (P &lt; 0.01), MDA (P &lt; 0.05), LDH (P &lt; 0.05) increased and SOD (P μmol/l, and the content of SOD is lower. Resveratrol has dose-dependent inhibition effects of the production of MDA, NO and LDH, and it can significantly increase the content of SOD (5μmol/l vs 10μmol/l, P &lt; 0.001). The content of MDA, NO and LDH of 48h resveratrol group is lower than the 24 hour resveratrol group (P &lt; 0.05). There were also difference between the two groups of atovastatin. <h3>Conclusions</h3> Resveratrol and atovastatin both have dose and time-dependent anti-oxidative effects. Resveratrol is more powerful in anti-oxidative stress activity than atovastatin. Resveratrol is a promising drug for the prevention and treatment of atherosclerosis in the future.

Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene

Hepatic hydroxymethyl glutary coenzyme A HMG-CoA reductase inhibitors (statins) have various anti atherosclerosis pleiotropic effects that are independent of cholesterol reduction. Human serum paraoxonase 1 (PON1) is associated with high-density lipoprotein (HDL) and inhibits the oxidative modification of low-density lipoprotein (LDL). We investigated the effects of statins on PON1 gene transcription using a reporter gene assay. Promoter activity of the PON1 gene was estimated by measuring luciferase activity of plasmids with a PON1 promoter region transfected into human hepatoma HepG2 cells and human embryonic kidney (HEK) 293 cells. Pitavastatin, simvastatin, and atorvastatin each significantly increased PON1 promoter activity, and the transactivation by pitavastatin was abrogated by mevalonic acid and farnesyl pyrophosphate (FPP), however, not by geranylgeranyl pyrophosphate. Further, PON1 promoter activity was enhanced by farnesyl transferase inhibitor (FTI), but not by geranylgeranyl transferase inhibitor (GGTI). PON1 gene transcription has been reported to be dependent on Sp1 and the transactivation by pitavastatin was completely abrogated by mithramycin, an inhibitor of Sp1. Our results suggest that pitavastatin activates transcription of the PON1 gene through the FPP pathway, which may play an important role in the anti atherosclerotic effects of statins.