Potential Anti-atherosclerotic Effects Research Articles

Baoyuan decoction inhibits atherosclerosis progression through suppression peroxidized fatty acid and Src/MKK4/JNK pathway-mediated CD 36 expression

Background: Baoyuan decoction (BYD) has been widely utilized as a traditional prescription for the treatment of various conditions such as coronary heart disease, aplastic anemia, and chronic renal failure. However, its potential efficacy in improving atherosclerosis has not yet been investigated.Purpose: Our research aimed to assess the potential of BYD as an inhibitor of atherosclerosis and uncover the underlying mechanism by which it acts on foam cell formation.Study Design and Methods: High-fat diet-induced ApoE-/- mice were employed to explore the effect of BYD on atherosclerosis. The differential metabolites in feces were identified and analyzed by LC-Qtrap-MS. In addition, we utilized pharmacological inhibition of BYD on foam cell formation induced by oxLDL in THP-1 cells to elucidate the underlying mechanisms specifically in macrophages.Results: The atherosclerotic plaque burden in the aortic sinus of ApoE-/- mice was notably reduced with BYD treatment, despite no significant alterations in plasma lipids. Metabolomic analysis revealed that BYD suppressed the increased levels of peroxidized fatty acids, specifically 9/13-hydroxyoctadecadienoic acid (9/13-HODE), in the feces of mice. As a prominent peroxidized fatty acid found in oxLDL, we confirmed that 9/13-HODE induced the overexpression of CD36 in THP-1 macrophages by upregulating PPARγ. In subsequent experiments, the decreased levels of CD36 triggered by oxLDL were observed after BYD treatment. This decrease occurred through the regulation of the Src/MMK4/JNK pathway, resulting in the suppression of lipid deposition in THP-1 macrophages.Conclusions: These results illustrate that BYD exhibits potential anti-atherosclerotic effects by inhibiting CD36 expression to prevent foam cell formation.

The Complex Mechanisms and the Potential Effects of Statins on Vascular Calcification: A Narrative Review.

Vascular calcification (VC) is a complex process of calcium deposition on the arterial wall and atherosclerotic plaques and involves interaction between vascular smooth muscle cells, inflammatory and VC mediators. The latter are independent predictors of cardiovascular morbidity and mortality and potential targets of pharmaceutical therapy. This paper is a narrative review of the complex mechanisms of VC development and in this context the potential anti-atherosclerotic effects of statins. At the initial stages of atherosclerosis VC correlates with atherosclerosis burden and in the long-term with cardiovascular morbidity and mortality. A plethora of animal and clinical studies have proposed statins as the cornerstone of primary and secondary prevention of atherosclerotic cardiovascular disease. Based on coronary computed tomography data, high doses of statins may have negligible or even positive effects on the progression of coronary artery calcification. Growing data support an increase in atherosclerotic plaque calcification in peripheral arteries (e.g., carotids), after long-term, statin-therapy. Despite the paradox of increasing VC, those effects of statins have been associated with higher plaque stability, reducing the risk of consequent adverse events. Statins seem to promote a "favorable" atherosclerotic calcification, suppressing atherosclerotic lesion expansion and their vulnerability. More studies are required to clarify the underlying mechanisms.

Potensi Padina australis sebagai Marine Drug untuk Aterosklerosis

<p><em>Atherosclerosis is characterized by endothelial dysfunction, altered lipid accumulation, inflammation, and foam cells deposition. Fucoxanthin and fucoidan that are contained in Padina australis are known to have potential anti-atherosclerotic effects. This review aims to see the activity and potential of Padina australis as an anti-atherosclerotic marine drug. This literature review article was obtained through a online-based scientific database using terms or phrases relevant to the topic. Fucoxanthin reduces ROS and inhibits production of NO, PGE2, TNF-α, IL-6, and IL-1β. Meanwhile, fucoidan can regulate the development of atherosclerosis by preventing SMC from forming foam cells, LOX-1 expression, and proinflammatory molecules significantly. A decrease in total cholesterol, triglycerides, LDL, and increased HDL-c also shown to be one of the effects of fucoidan in modulating lipid metabolism. Fucoxanthin can increase thermogenesis by increasing PRDM16, UCP-1, and UCP-3 in BAT and decreasing adipocyte size, leptin, and increasing adiponectin in WAT. Fucoidan can lower the cholesterol index, triglycerides, LDL, and increase the expression of PPARγ which can increase lipid metabolism and inhibit hyperlipidemia. In conclusion, Padina australis is potential anti-atherosclerosis agent due to its fucoxanthin and fucoidan exhibiting antioxidant, anti-inflammatory effects, and modulation of lipid metabolism.</em></p><p><em>Keywords: Padina australis, </em><em>f</em><em>ucoxanthin, </em><em>f</em><em>ucoidan, </em><em>a</em><em>therosclerosis, marine </em><em>d</em><em>rug</em></p>

Efficacy and Safety of Cilostazol for Atherosclerosis: A Meta-analysis of Randomized Controlled Trials.

To investigate the efficacy and safety of cilostazol for atherosclerosis. PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to May 29, 2021, were searched for randomized clinical trials (RCTs). Ten trials with 1577 patients were included. Treatment with cilostazol significantly reduced carotid intima-media thickness [mean difference (MD), -0.12 mm; 95% confidence interval (CI), -0.17 to -0.06]. According to the difference in intervening measures, the cilostazol group was superior to the control group in inhibiting the progression of carotid intima-media thickness: cilostazol versus placebo (MD, -0.04 mm; 95% CI, -0.06 to -0.02; P < 0.00001), cilostazol versus no antiplatelet drug (MD, -0.14 mm; 95% CI, -0.26 to -0.03; P = 0.02), cilostazol versus aspirin (MD, -0.17 mm; 95% CI, -0.32 to -0.02; P = 0.02), cilostazol + aspirin versus aspirin (MD, -0.08 mm; 95% CI, -0.14 to -0.02; P = 0.007), cilostazol + aspirin versus clopidogrel + aspirin (MD, -0.07 mm; 95% CI, -0.14 to -0.00; P = 0.04), and cilostazol + clopidogrel + aspirin versus clopidogrel + aspirin (MD, -0.16 mm; 95% CI, -0.30 to -0.02; P = 0.03). Cilostazol treatment considerably decreased triglyceride (MD, -20.18 mg/dL; 95% CI, -39.03 to -1.34) and improved high-density lipoprotein cholesterol (MD, 4.35 mg/dL; 95% CI, 2.61-6.10). Cilostazol therapy significantly increased the risk of adverse events of headache (odds ratio, 12.91; 95% CI 5.33-31.29). Our research has revealed that cilostazol has potent antiatherosclerotic effects and can reverse atherosclerosis progress even in high-risk patients, such as those with type 2 diabetes mellitus, and does not increase the risk of bleeding.

Lycopene Reduces Cholesterol Absorption and Prevents Atherosclerosis in ApoE-/- Mice by Downregulating HNF-1α and NPC1L1 Expression.

Our previous study showed that lycopene reduced the absorption of cholesterol in Caco-2 cells through inhibiting Niemann-Pick C1-Like 1 (NPC1L1) expression. Herein, we aimed to explore whether lycopene supplementation can decrease cholesterol absorption in the intestine and prevent atherosclerosis progression in high-fat diet (HFD)-fed apolipoprotein E knockout (ApoE-/-) mice. Male ApoE-/- mice were fed a high-fat diet with or without lycopene for 19 weeks. Supplementation of lycopene markedly lowered serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. Additionally, serum high-density lipoprotein cholesterol (HDL-C) levels were increased after lycopene administration. Lycopene also downregulated the expression of NPC1L1 and hepatocyte nuclear factor-1α (HNF-1α) in the small intestine. Furthermore, the Oil Red O staining of the aorta and aortic sinus showed that lycopene supplementation remarkably reduced atherosclerotic lesions. These results indicated that lycopene inhibited intestinal cholesterol absorption and protected against HFD-induced atherosclerosis through inhibiting HNF-1α and NPC1L1 expression. Lycopene exhibits a potential antiatherosclerotic effect through suppressing intestinal cholesterol absorption.

Yixintongmai Inhibits Proliferation and Migration and Promotes Apoptosis of Vascular Smooth Muscle Cells Cultured with High Glucose.

Objective This study was designed to evaluate the effects of yixintongmai on proliferation, migration, and apoptosis of vascular smooth muscle cells (VSMCs) cultured with high glucose. Methods VSMCs of the thoracic aorta from 5- to 8-week-old male Sprague-Dawley rats were cultured with normal (4.5 mM) or high (25 mM) glucose, respectively. The concentration of yixintongmai powder at 360 μg/ml was chosen according to pre-experimental results. Results Yixintongmai inhibited the proliferation of VSMCs (CCK-8 assay: 0.75 ± 0.04 versus 0.98 ± 0.09 OD, P < 0.001; cell counting: 37533 ± 1861 versus 56009 ± 3779 cells/well, P < 0.001) and the expression of proliferating cell nuclear antigen (0.74 ± 0.08 fold, P < 0.001) as compared with high glucose (HG). Yixintongmai inhibited the migration of VSMCs (transwell assay: 146 ± 16 versus 265 ± 62 cells; P < 0.001), scratch wound assay (0.17 ± 0.01 fold, P < 0.001), and the expression of matrix metalloproteinases-9 (0.87 ± 0.03 fold, P < 0.001) as compared with HG. Yixintongmai decreased mitochondrial membrane potentials (0.36 ± 0.12 fold, P < 0.001) and promoted early (2.11 ± 0.20 fold, P < 0.01) and late (2.11 ± 0.28 fold, P < 0.01) apoptosis of VSMCs as compared with HG. Yixintongmai inhibited the expression of B-cell lymphoma 2 (0.83 ± 0.07 fold, P < 0.01) and stimulated the activity of cleaved-capase-3/caspase-3 (2.00 ± 0.12 fold, P < 0.05) as compared with HG. Yixintongmai inhibited reactive oxygen species generation (0.46 ± 0.03 fold, P < 0.01) and the expression of NADPH oxidase-1 (0.84 ± 0.04 fold, P < 0.001), nuclear factor-kappa B (NF-κB) p65 (0.71 ± 0.07 fold, P < 0.001), phosphorylated NF-κB p65 (0.39 ± 0.02 fold, P < 0.0001), and inhibited nuclear translocation of NF-κB p65 (0.87 ± 0.03 fold, P < 0.001) in VSMCs as compared with HG. Conclusions Yixintongmai inhibits the proliferation and migration and promotes the apoptosis of VSMCs cultured with HG, which suggests the potential anti-atherosclerotic effects of this traditional Chinese medicine.

Juglanin suppresses oscillatory shear stress-induced endothelial dysfunction: An implication in atherosclerosis

IntroductionAtherosclerosis is characterized by endothelial cell dysfunction followed by lesion formation, arterial stenosis, potentially arterial occlusion, and severe outcomes. Novel treatments to slow or prevent the progression of the disease are of considerable clinical value. In the present study, we investigated the potential anti-atherosclerotic effects of the natural product juglanin in oscillatory shear stress (OSS) exposed endothelial cells. MethodsHuman aortic endothelial cells (HAECs) were exposed to OSS generated by a micro fluidal Teflon cone at 1 Hz frequency cycles (±5 dyn/cm2) in the presence or absence of 2.5 and 5 μM juglanin for 24 h. The expression levels of inflammatory factors and vascular adhesion molecules were evaluated using qRT-PCR, Western Blot, and ELISA. DHE assay was used to detect the production of ROS. The monocytic THP-1 cells were labeled with calcein-AM and incubated with HAECs for adhesion assay. ResultsJuglanin reduces OSS-induced oxidative stress by reducing the production of ROS through downregulation of NOX-2 and rescuing OSS-induced reduced expression of eNOS. Juglanin also inhibits the inflammatory response by suppressing OSS-induced expressions of IL-1β, MCP-1, and HMGB1. Using THP-1 monocytes, we show that juglanin reduces the attachment of monocytes to endothelial cells by inhibiting the expression of VCAM-1 and E-selectin. Moreover, Juglanin rescues OSS-reduced expression of atheroprotective transcriptional factor KLF2. ConclusionsOur findings indicate that juglanin protects against various atheroprone OSS-induced endothelial dysfunction. Juglanin has potential implication as a candidate for vascular intervention of atherosclerosis.

The protective effects of angelica organic acid against ox-LDL-induced autophagy dysfunction of HUVECs

BackgroundAngelica root is the dry root of the Umbelliferae plant Angelica sinensis (oliv) Diels. Angelica organic acid (OA) is the main active ingredient in Angelica sinensis, and it exerts potential anti-atherosclerotic effects by preventing Oxidized low-density lipoprotein (Ox-LDL) induced endothelial injury. To study the protective effects of OA on ox-LDL-induced HUVECs autophagic flux dysfunction and inflammatory injury.MethodsOA were isolated by water extraction and alcohol precipitation, and then the content of ferulic acid (FA) in the OA was determined by high performance liquid chromatography. The ox-LDL-induced endothelial injury model was established. The effect of ferulic acid on the survival of Human umbilical vein endothelial cells (HVUECs) was detected by CCK-8 assay. HUVECs were pretreated with different concentrations of OA (20 μmol/L, 40 μmol/L, and 80 μmol/L), and Western Blot was used to detect the expressions of LC3II, p62, MCP-1, VCAM-1 and LOX-1. The autophagosomes in HUVECs were observed by transmission electron microscopy (TEM).Results20 μmol/L OA could increase the expression of LC3II and decrease the expression of p62, MCP-1, VCAM-1 and LOX-1. The results of TEM showed that angelica organic acids promoted cell organelle degradation in autolysosomes.ConclusionOA could reduce inflammation, protect endothelial cells and play an anti-atherosclerotic role by enhancing the autophagy flux of damaged endothelial cells, in which FA the major active ingredient of OA played a major role.

MP59-19 ANTI-ATHEROSCLEROTIC EFFECT OF EVEROLIMUS IN KIDNEY-TRANSPLANTED PATIENTS

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation & Vascular Surgery III (MP59)1 Apr 2020MP59-19 ANTI-ATHEROSCLEROTIC EFFECT OF EVEROLIMUS IN KIDNEY-TRANSPLANTED PATIENTS Takeshi Ishimura*, Takahito Endo, Shun Nishioka, Naoki Yokoyama, Teruyuki Oda, Satoshi Ogawa, and Masato Fujisawa Takeshi Ishimura*Takeshi Ishimura* More articles by this author , Takahito EndoTakahito Endo More articles by this author , Shun NishiokaShun Nishioka More articles by this author , Naoki YokoyamaNaoki Yokoyama More articles by this author , Teruyuki OdaTeruyuki Oda More articles by this author , Satoshi OgawaSatoshi Ogawa More articles by this author , and Masato FujisawaMasato Fujisawa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000928.019AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cardiovascular disease (CVD) is the major cause of death after kidney transplantation (KTx). Everolimus (EVR) is an immunosuppressive agent now widely used in KTx that is also known for its anti-atherosclerotic effect. The Ankle–Brachial Index (ABI), Carotid Artery Intima–Media Thickness (IMT), and Cardioankle Vascular Index (CAVI) provide indicators of atherosclerosis and are utilized as surrogate CVD markers in many diseases such as chronic kidney disease and diabetes. In this study, we explored the potential anti-atherosclerotic effect of EVR in KTx by sequentially assessing the ABI, IMT, and CAVI. METHODS: This study included 107 patients who recently underwent KTx with triple immunosuppression therapy consisting of calcineurin inhibitor (CNI, either tacrolimus or cyclosporine), mycophenolate mofetil, and methylprednisolone. Three months after KTx, EVR was added in 52 patients (EVR+ group), and 55 patients remained on conventional CNI-based immunosuppression therapy without EVR (EVR- group). The ABI, IMT (mm), and CAVI were examined 3 months and 1 year after KTx, and the mean of the right and left values of each test were regarded as an index of atherosclerosis. The changes in the values of each test from 3 months to 1 year were compared between the EVR+ and EVR- groups. Additionally, we determined the prognostic significance of EVR use in the progression of atherosclerosis as well as other clinical parameters. RESULTS: Overall, the mean ABI, IMT, and CAVI 3 months and 1 year after KTx were 1.125 ± 0.087 (n=107) and 1.137 ± 0.091 (n=100), 0.650 ± 0.199 (n=107) and 0.633 ± 0.310 (n=92), and 7.579 ± 1.348 (n=70) and 7.493± 1.623 (n=63), respectively; no significant differences from 3 months to 1 year were observed in each test. The changes in the ABI, IMT, and CAVI in the EVR+ vs. EVR- groups were 0.044 ± 0.093 vs. -0.011 ± 0.087 (p=0.003), -0.022 ± 0.127 vs. 0.033 ± 0.361, and 0.023 ± 1.487 vs. -0.173 ± 1.322, respectively. The ABI in the EVR- group showed a significant reduction from 3 months to 1 year than that in the EVR+ group. Furthermore, EVR non-use, high total cholesterol 3 months after KTx, and cyclosporine use were revealed as prognostic factors for a reduction in the ABI; however, the only independent prognostic factor determined on multivariate analysis was high total cholesterol 3 months after KTx. CONCLUSIONS: The results suggest that the early addition of EVR may prevent atherosclerosis progression after KTx. Further studies in more patients with a longer observation period may provide evidence of the anti-atherosclerotic effect of EVR. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e888-e888 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takeshi Ishimura* More articles by this author Takahito Endo More articles by this author Shun Nishioka More articles by this author Naoki Yokoyama More articles by this author Teruyuki Oda More articles by this author Satoshi Ogawa More articles by this author Masato Fujisawa More articles by this author Expand All Advertisement PDF downloadLoading ...

Tiaopi huxin recipe improved endothelial dysfunction and attenuated atherosclerosis by decreasing the expression of caveolin-1 in ApoE-deficient mice.

The Tiaopi Huxin recipe (TPHXR) is widely used in traditional Chinese medicine for the clinical treatment of coronary heart disease. However, the mechanism of TPHXR treatment of atherosclerosis (AS) has not been fully elucidated. In this study, we have aimed to explore the potential antiatherosclerotic effect of TPHXR and its underlying mechanisms. Male ApoE knockout (ApoE-/- ) mice were fed a high-fat diet for 12 weeks and were randomly divided into four groups: the control group, and the low-dose, medium-dose, and high-dose TPHXR groups. The nitric oxide (NO) levels in arterial tissue and human umbilical vein endothelial cells (HUVECs) were measured bydiaminofluorescein-2 diacetate staining. Vasorelaxation of mice aorta was performed by wire myograph. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), hs-CRP, IL-6, and IL-1β, in mice plasma were analyzed by enzyme-linked immunosorbent assay. Western blot analysis was applied to observe protein expression. Oil Red O staining was utilized for the quantification of atherosclerotic plaques. Results showed that 4 weeks of high- and medium-dose TPHXR treatment by oral gavage reduced atheromatous lesions in ApoE -/- mice. The high- and medium-dose TPHXR treatment, but not the low-dose treatment, promoted eNOS phosphorylation, increased NO levels and improved endothelium-dependent vasorelaxation in ApoE -/- mice. High- and medium-dose TPHXR, but not low-dose TPHXR, decreased the expression of cav-1, NF-κB p50, NF-κB p65, ICAM1, VCAM-1, TNF-α, IL-6, and IL-1β in the vasculature of ApoE -/- mice. Enzyme-linked immunosorbent assay analysis indicated that high- and medium-dose TPHXR decreased the levels of TNF-α, IL-6, hs-CRP, and IL-1β. In conclusion, our findings show that TPHXR improved the endothelial function and reduced atheromatous lesions in ApoE -/- mice. This result may be due to the decreased expression of caveolin-1 and NF-κB and, hence, the attenuated inflammatory response in AS mice vasculature. TPHXR may represent a promising intervention in patients with AS.

Atherosclerosis in Rheumatoid Arthritis: Promoters and Opponents.

Substantial epidemiological data identified cardiovascular (CV) diseases as a main cause of mortality in patients with rheumatoid arthritis (RA). In light of this, RA patients may benefit from additional CV risk screening and more intensive prevention strategies. Nevertheless, current algorithms for CV risk stratification still remain tailored on general population and are burdened by a significant underestimation of CV risk in RA patients. Acute CV events in patients with RA are largely related to an accelerated atherosclerosis. As pathophysiological features of atherosclerosis overlap those occurring in the inflamed RA synovium, the understanding of those common pathways represents an urgent need and a leading challenge for CV prevention in patients with RA. Genetic background, metabolic status, gut microbiome, and systemic inflammation have been also suggested as additional key pro-atherosclerotic factors. The aim of this narrative review is to update the current knowledge about pathophysiology of atherogenesis in RA patients and potential anti-atherosclerotic effects of disease-modifying anti-rheumatic drugs.

A major daidzin metabolite 7,8,4′-trihydroxyisoflavone found in the plasma of soybean extract-fed rats attenuates monocyte-endothelial cell adhesion

Among many functional foods and their phytochemicals, ingestion of soybean (Glycine max) is highly correlated to reduced risk of cardiovascular diseases. Validation of potential health benefits of functional foods requires information about the bioavailability and metabolism of bioactive compounds. In this context, several phase I and II metabolites of isoflavones were target-analyzed in the plasma of rats acutely supplemented with soybean embryo extract. A daidzein metabolite, 7,8,4′-trihydroxyisoflavone (7,8,4′-THI), was found to have the highest average area under curve value (574.3±112.8). Therefore, its potential prevention effect on atherosclerosis was investigated using monocyte-endothelial cell adhesion assay. Different from its precursor daidzein or daidzin, 7,8,4′-THI attenuated adhesion of THP-1 monocytes to tumor necrosis factor-alpha (TNF-α) stimulated human umbilical vein endothelial cells (HUVECs). In addition, 7,8,4′-THI significantly downregulated TNF-α stimulated the expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 and phosphorylation of IκB kinase and IκBα involved in the initiation of atherosclerosis in HUVECs. Therefore, 7,8,4′-THI, a highly bioavailable hydroxylated isoflavone metabolite, has potential anti-atherosclerotic effect via inhibiting monocyte-endothelial adhesion.

Resveratrol Ameliorates Arterial Stiffness Assessed by Cardio-Ankle Vascular Index in Patients With Type 2 Diabetes Mellitus.

Resveratrol has been reported to have potent anti-atherosclerotic effects in animal studies. However, there are few interventional studies in human patients with atherosclerogenic diseases. The cardio-ankle vascular index (CAVI) reflects arterial stiffness and is a clinical surrogate marker of atherosclerosis. The aim of the present study was to investigate the effect of resveratrol on arterial stiffness assessed by CAVI in patients with type 2 diabetes mellitus (T2DM).In this double-blind, randomized, placebo-controlled study, 50 patients with T2DM received supplement of a 100mg resveratrol tablet (total resveratrol: oligo-stilbene 27.97 mg/100 mg/day) or placebo daily for 12 weeks. CAVI was assessed at baseline and the end of study. Body weight (BW), blood pressure (BP), glucose and lipid metabolic parameters, and diacron-reactive oxygen metabolites (d-ROMs; an oxidative stress marker) were also measured.Resveratrol supplementation decreased systolic BP (-5.5 ± 13.0 mmHg), d-ROMs (-25.6 ± 41.8 U.CARR), and CAVI (-0.4 ± 0.7) significantly (P < 0.05) and decreased BW (-0.8 ± 2.1 kg, P = 0.083) and body mass index (-0.5 ± 0.8 kg/m2, P = 0.092) slightly compared to baseline, while there were no significant changes in the placebo group. Decreases in CAVI and d-ROMs were significantly greater in the resveratrol group than in the placebo group. Multivariate logistic regression analysis identified resveratrol supplementation as an independent predictor for a CAVI decrease of more than 0.5.In conclusion, 12-week resveratrol supplementation may improve arterial stiffness and reduce oxidative stress in patients with T2DM. Resveratrol may be beneficial in preventing the development of atherosclerosis induced by diabetes. However, a large-scale cohort study is required to validate the present findings.

Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence.

There is good epidemiological evidence that patients with autoimmune rheumatic disease states, particularly rheumatoid arthritis, have an increased risk of cardiovascular morbidity and mortality when compared to the general population. The presence of a chronic systemic proinflammatory state in this patient group disrupts the structural and functional integrity of the endothelium and the arterial wall, favouring the onset and progression of atherosclerosis. A significant role in the detrimental effects of inflammation on endothelial function and vascular homeostasis is played by specific proatherosclerotic cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). Recent systematic reviews and meta-analyses have shown that treatment with methotrexate, a first-line disease-modifying antirheumatic drug (DMARD), is associated with a significant reduction in atherosclerosis-mediated cardiovascular events, such as myocardial infarction and stroke, and mortality, when compared to other DMARDs. This suggests that methotrexate might exert specific protective effects against vascular inflammation and atherosclerosis in the context of autoimmune rheumatic disease. This review discusses the available evidence regarding the potential antiatherosclerotic effects of methotrexate through the inhibition of TNF-α, IL-1, and IL-6 and provides suggestions for future experimental and human studies addressing this issue.

Cepharanthine inhibits in vitro VSMC proliferation and migration and vascular inflammatory responses mediated by RAW264.7

Pathogenesis of atherosclerosis involves vascular smooth muscle cell (VSMC) migration and proliferation followed by an inflammation mediated by activated macrophages in the tunica intima of blood vessels. Cepharanthine (CEP) belongs to bisbenzylisoquinoline alkaloids found in the plant Stephania cepharantha, which has been used for various diseases like cancer, alopecia areata, venomous snakebites, and malaria. In this study, we investigated whether CEP suppresses VSMC migration and proliferation and inhibits inflammatory mediator production in macrophage (RAW264.7). Our results showed that CEP possessed significant DPPH scavenging and metal chelating activities. It also markedly inhibited lipid peroxidation. Similarly, CEP suppressed the nitric oxide (NO) production and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in RAW264.7 cells. Moreover, the level of prostaglandin E2 was also suppressed and the formation of macrophage derived foam cell was attenuated in RAW264.7 cells. Likewise, NO production in isolated peritoneal macrophage and VSMC migration in response to LPS stimulated RAW264.7 was also halted by CEP treatment. Also, VSMC migration induced by platelet-derived growth factor (PDGF-BB) was inhibited by CEP dose dependently. The anti-migratory effect of CEP on VSMCs was due to its inhibitory effect on metalloproteinase-9 (MMP-9) expression, preventing the degradation of extracellular matrix (ECM) component. Furthermore, CEP suppressed PDGF-BB induced VSMC proliferation by down-regulation of mitogen activated protein kinase (MAPK) signaling molecules. CEP also inhibited the translocation of NF-κB from cytosol to nucleus. Thus, our results suggest that CEP exerts potent anti-atherosclerotic effect through attenuation of inflammation, lipid peroxidation and VSMC migration and proliferation.

Pycnogenol attenuates atherosclerosis by regulating lipid metabolism through the TLR4-NF-κB pathway.

Atherosclerosis is a leading cause of death worldwide and is characterized by lipid-laden foam cell formation. Recently, pycnogenol (PYC) has drawn much attention because of its prominent effect on cardiovascular disease (CVD). However, its protective effect against atherosclerosis and the underlying mechanism remains undefined. Here PYC treatment reduced areas of plaque and lipid deposition in atherosclerotic mice, concomitant with decreases in total cholesterol and triglyceride levels and increases in HDL cholesterol levels, indicating a potential antiatherosclerotic effect of PYC through the regulation of lipid levels. Additionally, PYC preconditioning markedly decreased foam cell formation and lipid accumulation in lipopolysaccharide (LPS)-stimulated human THP-1 monocytes. A mechanistic analysis indicated that PYC decreased the lipid-related protein expression of adipose differentiation-related protein (ADRP) and adipocyte lipid-binding protein (ALBP/aP2) in a dose-dependent manner. Further analysis confirmed that PYC attenuated LPS-induced lipid droplet formation via ADRP and ALBP expression through the Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) pathway, because pretreatment with anti-TLR4 antibody or a specific inhibitor of NF-κB (PDTC) strikingly mitigated the LPS-induced increase in ADRP and ALBP. Together, our results provide insight into the ability of PYC to attenuate bacterial infection-triggered pathological processes associated with atherosclerosis. Thus PYC may be a potential lead compound for the future development of antiatherosclerotic CVD therapy.

Statin-induced coronary artery disease regression rates differ in men and women.

Whether statins are equi-efficacious in women and men continues to be debated. The potential antiatherosclerotic effects of high-intensity statin therapy on coronary atheroma in women compared with men have only very recently been characterized. This review aims to summarize the evidence underlying these recent observations. Coronary intravascular ultrasound (IVUS) is a highly sensitive plaque imaging tool, and serial changes of plaque burden on IVUS are known to associate with incident cardiovascular events. Study of coronary atheroma by intravascular ultrasound: effect of rosuvastatin versus atorvastatin was a randomized controlled trial employing serial IVUS to evaluate the antiatherosclerotic efficacy of high-dose rosuvastatin and atorvastatin during a 24-month study period. Study of coronary atheroma by intravascular ultrasound: effect of rosuvastatin versus atorvastatin revealed significantly greater coronary atheroma regression in women compared with men, particularly in the setting of lower achieved LDL cholesterol. Results of this analysis also identified a significant interaction between sex and type of statin used. These findings support the broad use of statins, especially high-intensity statins, in women with coronary artery disease, who may in fact derive greater benefit than men. These findings also suggest the need for dedicated clinical trials involving women, supporting the notion of more personalized therapeutic strategies for tackling atherosclerotic disease.

Pure peptides from amaranth (Amaranthus hypochondriacus) proteins inhibit LOX-1 receptor and cellular markers associated with atherosclerosis development in vitro

The objectives were to evaluate and to compare the effect of pure peptides from amaranth proteins on markers that promote atherosclerosis, in vitro. Amaranth pure peptides with potential anti-atherosclerotic effect, HGSEPFGPR, RPRYPWRYT and RDGPFPWPWYSH, were studied using lipopolysaccharide-induced THP-1 human macrophage-like cells. Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) expression was reduced by peptides HGSEPFGPR (83%), RDGPFPWPWYSH (49%) and RPRYPWRYT (63%); while intracellular adhesion molecule-1 (ICAM-1) was reduced by peptides RDGPFPWPWYSH (27%) and RPRYPWRYT (39%); and matrix metalloproteinase-9 (MMP-9) expression was reduced by 52% (HGSEPFGPR), 41% (RDGPFPWPWYSH) and 29% (RPRYPWRYT). Using confocal microscopy, peptide HGSEPFGPR reduced LOX-1, ICAM-1 and MMP-9 expression by 74%, 59% and 80%, respectively. RPRYPWRYT reduced LOX-1, ICAM-1 and MMP-9 expression by 48%, 49% and 71%, respectively. RPRYPWRYT reduced MCP-1 and TGF-β cellular protein expression (74% and 78%, respectively); 89% (IL-6 and IL-1α); 83% (IFN-γ); 87% and 58% (TNF-α and TNF-β). HGSEPFGPR showed significant reduction of 27%, 31%, 41%, 57%, and 61% for GRO-α, MCP-1, IL-6, IL-1α, and RANTES, respectively. HGSEPFGPR showed better interactions with LOX-1 crystal structure than RPRYPWRYT. Amaranth pure peptides reduced the expression of proteins associated with LOX-1 signaling pathway, in vitro.

EFEK ANTI ATEROSKLEROTIK ADIPONEKTIN

Atherosclerosis is a chronic, inflammatory disease of the arterial wall. Atherosclerosis underlies many of the common causes of cardiovascular morbidity and mortality, including myocardial infarction (MI), peripheral vascular disease, and cerebrovascular. Cardiovascular disease (CVD) has become the most frequent cause of death globally and then stroke is the second leading cause of death worldwide and a major cause of long-term disability. Recent study shows that adiponectin exhibits potent antiatherosclerotic effects. Adiponectin is a protein secreted specifically from adipose tissue. Adiponectin has a potential inhibitory effect on all molecular mechanisms of atherosclerosis.

1,25-dihydroxyvitamin D3 causes ADAM10-dependent ectodomain shedding of tumor necrosis factor receptor 1 in vascular smooth muscle cells.

1,25-Dihydroxyvitamin D3 (1,25D3) has a potential antiatherosclerotic effect through anti-inflammatory actions. We investigated how 1,25D3 regulates tumor necrosis factor-α (TNF-α)-induced lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in cultured human aortic smooth muscle cells. TNF-α activated Rac1/reactive oxygen species/spleen tyrosine kinase and transcriptional factors, activator protein-1, and nuclear factor κB, which led to LOX-1 expression. 1,25D3 inhibited TNF-α-induced LOX-1 expression by inhibiting Rac1 activation and thereby its downstream signals. 1,25D3 rapidly induced extracellular Ca(2+) influx. Verapamil, an inhibitor of L-type calcium channels, inhibited 1,25D3-induced Ca(2+) influx and counteracted the inhibitory effects of 1,25D3 on Rac1 activation, whereas Bay K8644 [1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid, methyl ester], an L-type calcium channel agonist, attenuated TNF-α-induced Rac1 activation, as 1,25D3 did. 1,25D3 induced the ectodomain shedding of TNF receptor 1 (TNFR1), which was abolished by verapamil and in Ca(2+)-free media. Like 1,25D3, Bay K8644 induced the ectodomain shedding of TNFR1. Both 1,25D3 and Bay K8644 caused the translocation of a disintegrin and metalloprotease (ADAM) 10 from the cytoplasm to the plasma membrane, which was dependent on extracellular Ca(2+) influx. In contrast, depletion of ADAM10 by transfection of ADAM10-small interfering RNA prevented 1,25D3- or Bay K8644-induced ectodomain shedding of TNFR1 and abolished the suppressive effect of 1,25D3 on TNF-α-induced Rac1 activation. Taken together, these findings suggest that 1,25D3 induces extracellular Ca(2+) influx via L-type calcium channel, triggering ADAM10-mediated ectodomain shedding of TNFR1, and it thereby decreases responsiveness to TNF-α. By shedding TNFR1 from the cell surface, 1,25D3 may regulate inflammation and atherogenesis, whereas this effect could be attenuated by calcium channel blockers.