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Angiology 02/2013; · 1.51 Impact Factor
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ABSTRACT: Although the role of the ubiquitin-proteasome system (UPS) in cardiac hypertrophy induced by pressure overload has been consistently studied, the fundamental importance of the UPS in cardiac fibrosis has received much less attention. Our previous study found that proteasome inhibitor (MG132) treatment attenuated cardiac fibrosis and heart failure during the early and middle stages of pressure overload. However, the effects of this inhibitor on late-stage pressure overload hearts remain unclear and controversial. The present study was designed to investigate the effects and possible mechanisms of MG132 on cardiac fibrosis and dysfunction during the late stages of pressure overload. Male Sprague Dawley rats with abdominal aortic constriction (AAC) or a sham operation received an intraperitoneal injection of MG132 (0.1 mgkg(-1)day(-1)) or vehicle for 16 weeks. Left ventricular (LV) function, collagen deposition and Ang II levels were evaluated at study termination. Ang II-stimulated adult rat cardiac fibroblasts were utilized to examine the effects of MG132 on collagen synthesis and the relationship between the renin-angiotensin- aldosterone system (RAAS) and the UPS. MG132 treatment attenuated ventricular dysfunction by suppressing cardiac fibrosis rather than inhibiting cardiac hypertrophy during the late-stages of pressure overload. We also found that Ang II activates UPS in the heart and MG132 attenuates Ang II-induced collagen synthesis via suppression of the NF-κB/TGF-β/Smad2 signaling pathways. Proteasome inhibition therefore could provide a new promising therapeutic strategy to prevent cardiac fibrosis and progression of heart failure even during the late-stages of pressure overload.
Biochemical pharmacology 11/2012; · 4.25 Impact Factor
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ABSTRACT: Aim: The SYNTAX score is a semi-quantitative angiographic tool used to determine the extent and severity of coronary artery disease (CAD). Automatic computer-assisted measurement of the brachial-ankle pulse wave velocity (baPWV) is a reproducible and valid method by which to assess arterial stiffness. Limited information is available for the association between the SYNTAX score and arterial stiffness in a CAD patient. We aim to assess the association between arterial stiffness determined by PWV and CAD severity assessed by angiography and the SYNTAX score.Methods: 321 subjects underwent measurement of both baPWV and angiography from 2010 to 2011. BaPWV was divided into tertiles. Multiple logistic and linear regression analyses were used to evaluate the relationship between the SYNTAX score and baPWV.Results: After adjusting for age, body mass index, smoking habits, family history of CAD, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), total cholesterol, triglycerides, LDL-cholesterol, fasting glucose, serum creatinine, uric acid and cysteine proteinase, analyses revealed that baPWV groups were significantly associated with the SYNTAX score. Compared with the lowest baPWV tertile, the adjusted odds ratios (ORs) of having a SYNTAXHIG for the MID and HIG baPWV tertiles were 4.76 (95% confidence interval: 1.71-6.33) and 4.13 (95% confidence interval: 1.12-5.27), respectively. We also used multiple linear regression analyses to assess the association between baPWV and the SYNTAX score, which showed that baPWV was associated with the SYNTAX score.Conclusion: Arterial stiffness determined by PWV is related to CAD severity assessed by angiography and the SYNTAX score.
Journal of atherosclerosis and thrombosis 07/2012; · 2.69 Impact Factor
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ABSTRACT: Microglial activation plays an important role in neuroinflammation, which contributes to neuronal damage, and inhibition of microglial activation may have therapeutic benefits that could alleviate the progression of neurodegeneration. Recent studies have indicated that the antimalarial agent artemisinin has the ability to inhibit NF-κB activation. In this study, the inhibitory effects of artemisinin on the production of proinflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated primary microglia. Our results show that artemisinin significantly inhibited LPS-induced production of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1) and nitric oxide (NO). Artemisinin significantly decreased both the mRNA and the protein levels of these pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) and increased the protein levels of IκB-α, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Artemisinin treatment significantly inhibited basal and LPS-induced migration of BV-2 microglia. Electrophoretic mobility shift assays revealed increased NF-κB binding activity in LPS-stimulated primary microglia, and this increase could be prevented by artemisinin. The inhibitory effects of artemisinin on LPS-stimulated microglia were blocked after IκB-α was silenced with IκB-α siRNA. Our results suggest that artemisinin is able to inhibit neuroinflammation by interfering with NF-κB signaling. The data provide direct evidence of the potential application of artemisinin for the treatment of neuroinflammatory diseases.
PLoS ONE 01/2012; 7(4):e35125. · 4.09 Impact Factor
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ABSTRACT: Elevated serum bilirubin concentrations protect from atherosclerotic diseases, however it is not clear whether or not higher serum bilirubin concentrations have the same effect in coronary artery disease (CAD). The brachial-ankle pulse wave velocity (baPWV) is a reproducible method to assess arterial stiffness. This study was aimed to investigate the relationship between serum total bilirubin (TB) and baPWV in patients with established CAD.
We enrolled 638 patients (390 men, 248 women) with established CAD. TB was divided into tertiles. Simple and multiple linear regression analyses were used to assess the correlation between baPWV and TB.
The mean baPWV tended to decrease in men according to TB tertiles: Tertile 1=2,126.0, Tertile 2=1,832.5, and Tertile 3=1,692.5 cm/s. Likewise, the mean baPWV tended to decrease in women according to TB tertiles: Tertile 1=1,920.8, Tertile 2=1,829.0, and Tertile 3=1,701.3 cm/s. Univariate analysis showed that age, BMI, TB, ALT, GGT, Cho, SBP, DBP, UA, and TC were significantly associated with baPWV in men. In women, age, BMI, current smoker, Cho, SBP, DBP, UA, TC, TG, HDL-C, and LDL-C were significantly associated with baPWV. BMI, LnSBP, UA, TB, LnCho, and LnTC were correlated with baPWV in men in the multivariate model. However, only LnSBP, UA, and LnHDL-C were correlated with baPWV in women. TB was found to be a significant determinant for decreased baPWV only in men (β=-0.136; p<0.001).
Our findings show that the level of total serum bilirubin is negatively correlated with arterial stiffness in men with established CAD.
Internal Medicine 01/2012; 51(16):2083-9. · 0.94 Impact Factor
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ABSTRACT: High serum uric acid (SUA) has been well demonstrated to be associated with morbidity and mortality in the general population as well as in patients with coronary artery disease (CAD). Recent studies show that the clinical SYNTAX score (CSS) is a new tool for the risk stratification of patients with complex CAD. In this study, we aimed to evaluate whether SUA was associated with the complexity of CAD as evaluated by the CSS.
The study population consisted of 451 patients (69% male) who underwent coronary angiography for the assessment of CAD. A lesion was defined as significant if it caused a 50% reduction of the luminal diameter by visual estimation in vessels ≥1.5 mm. CSS was calculated by multiplying the SYNTAX score by a modified value of age, creatinine, and ejection fraction (ACEF) score (age/ejection fraction +1 for each 10 mL the creatinine clearance <60 mL/min per 1.73 m²).
All subjects were divided into three groups according to CSS tertiles: CSSLOW (CSS 2-11; n = 147), CSSMID (CSS 12-21; n = 152), and CSSHIGH (CSS 22-68; n = 152). The SUA level was prominently related with CSS (5.29 ± 1.23 mg/dL, 6.92 ± 1.23 mg/dL, and 8.31 ± 1.46 mg/dL; P<.001). SUA was a significant predictor of CSS after adjustment for other risk factors (OR, 2.68; P<.001).
SUA level was significantly associated with the severity and complexity of CAD evaluated by CSS. Further prospective clinical studies are needed to clarify the exact physiopathologic role of SUA in CAD.
The Journal of invasive cardiology 12/2011; 23(12):501-4. · 1.84 Impact Factor
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ABSTRACT: We aimed to investigate the regulation and contribution of vascular endothelial growth factor (VEGF) and sFlt-1(1-3) to human monocytic THP-1 migration.
Ad-sFlt-1/FLAG, a recombinant adenovirus carrying the human sFlt-1(1-3) (the first three extracellular domains of FLT-1, the hVEGF receptor-1) gene, was constructed. L929 cells were infected with Ad-sFlt-1/FLAG and the expression of sFlt-1 was detected by immunofluorescent assay and ELISA. Corning(®) Transwell(®) Filter Inserts containing polyethylene terephthalate (PET) membranes with pore sizes of 3 μm were used as an experimental model to simulate THP-1 migration. Five VEGF concentrations (0, 0.1, 1, 10 and 100 ng/ml), four concentrations of sFlt-1(1-3)/FLAG expression supernatants (0.1, 1, 10 and 100 ng/ml), and monocyte chemoattractant protein-1 (MCP-1, 10 ng/ml) were used to test the ability of THP-1 cells to migrate through PET membranes.
The sFlt-1(1-3) gene was successfully recombined into Ad-sFlt-1/FLAG. sFlt-1(1-3) was expressed in L929 cells transfected with Ad-sFlt-1/FLAG. THP-1 cell migration increased with increasing concentrations of VEGF, while cell migration decreased with increasing concentrations of sFlt1(1-3)/FLAG. sFlt1(1-3)/FLAG had no effect on MCP-1-induced cell migration.
This study demonstrated that VEGF is able to elicit a migratory response in THP-1 cells, and that sFlt-1(1-3) is an effective inhibitor of THP-1 migration towards VEGF.
Agents and Actions 04/2011; 60(8):769-74. · 1.59 Impact Factor
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ABSTRACT: Although MG132, a proteasome inhibitor, is suggested to impede secondary cardiac remodeling after hypertension, the mechanism and optimal duration of treatment remain unknown. This study was designed to investigate the effects and possible mechanism of MG132 on hypertension-induced cardiac remodeling. Male Sprague-Dawley rats subjected to abdominal aortic constriction (AAC) or sham operation received an intraperitoneal injection of MG132 (0.1mgkg(-1)day(-1)) or vehicle over a 2- or 8-week period. In the end, left ventricular (LV) function was evaluated with echocardiography and pressure tracing. Collagen deposition within the LV myocardium was assessed with Masson's trichrome staining. Ubiquitin-proteasome system (UPS), NF-κB, I-κB, TGFβ1 and Smad2 within the LV tissue were evaluated. In addition, angiotensin II within both plasma and LV tissue was also examined. Compared with the sham groups, the vehicle-treated AAC group exhibited a higher angiotensin II level, LV/body weight ratio, septal and posterior wall thicknesses, and a markedly reduced cardiac function (P<0.05). Treatment with MG132 for 8 weeks attenuated these cardiac remodeling parameters and improved cardiac function (P<0.01). 2- and 8-week hypertension led to activation of UPS, which was followed by activation of NF-κB and increased expression of TGFβ1 and Smad2 (P<0.01). MG132 significantly inhibited NF-κB activity and down-regulate the levels of TGFβ1 and Smad2 expression by 2 and still at 8 weeks (P<0.01). Short- and long-term treatment with MG132 significantly attenuated hypertension-induced cardiac remodeling and dysfunction, which may be mediated by the NF-κB/TGFβ1 signaling pathway.
Biochemical pharmacology 03/2011; 81(10):1228-36. · 4.25 Impact Factor
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Junqiang Yan,
Yunqi Xu,
Cansheng Zhu,
Limin Zhang,
Aimin Wu,
Yu Yang, Zhaojun Xiong,
Chao Deng,
Xu-Feng Huang,
Midori A Yenari,
Yuan-Guo Yang,
Weihai Ying,
Qing Wang
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ABSTRACT: In addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA) receptors interact closely with the dopaminergic system and are strongly implicated in therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors.
Regional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by [³H]MK-801(Dizocilpine) binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area), amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine) lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9), and TNF-a (tumour necrosis factor-alpha).
Our results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD via NMDA receptors.
PLoS ONE 01/2011; 6(6):e20945. · 4.09 Impact Factor
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ABSTRACT: The nuclear factor (NF)-κB signaling pathway is an important intracellular mediator of cardiac hypertrophy. Recent studies have indicated that the anti-malarial agent artemisinin has the ability to inhibit NF-κB activation. We hypothesized that artemisinin would suppress cardiac hypertrophy by inhibiting NF-κB signal pathways. We tested this hypothesis using primary cultured rat cardiac myocytes and well-established rat models of cardiac hypertrophy. Artemisinin blocked angiotensin II-induced cardiac hypertrophy in vitro in a concentration-dependent manner. Furthermore, artemisinin protected against rat cardiac hypertrophy induced by transaortic constriction (TAC), as assessed by heart weight/body weight and lung weight/body weight ratios, echocardiographic parameters, and gene expression of hypertrophic markers. Electrophoretic mobility shift assays revealed increased NF-κB binding activity in cardiac nuclear extracts of banded rats that was prevented by artemisinin treatment. Banded rats treated with oral artemisinin, compared with untreated rats, showed significantly decreased the levels of IL-6, TNF-α and MCP-1 mRNA expression and increased protein levels of IκB-α, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. The effect of artemisinin on cardiac hypertrophy was blocked after IκB-α was silenced by transfection of cardiomyocytes with IκB-α siRNA. Our results indicate that artemisinin inhibits cardiomyocyte growth by interfering with NF-κB signaling.
European journal of pharmacology 12/2010; 649(1-3):277-84. · 2.59 Impact Factor
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ABSTRACT: Proteasome inhibitors are involved in cell cycle control, growth and inflammatory signaling, and transcriptional regulation of mitotic cells. A recent study has suggested that specific proteasome inhibitor MG132 may suppress cardiomyocyte hypertrophy in vitro. However, the underlying molecular mechanisms are not clear. In this study, we investigated the effects of long-term MG132 treatment on cardiac hypertrophy and the related molecular mechanisms in vivo. MG132 (0.1 mg/kg/day) was intraperitoneally injected to rats with abdominal aortic banding (AAB) for 8 weeks. Results showed that treatment with MG132 significantly attenuated left ventricular (LV) myocyte area, LV weight/body weight, and lung weight/body weight ratios, decreased LV diastolic diameter and wall thickness, and increased fractional shortening in AAB rats. AAB induced the phosphorylation of ERK1/2, JNK1, and p38 in cardiac myocytes. The elevated phosphorylation levels of ERK1/2 and JNK1 in AAB rats were significantly reversed by MG132 treatment. In conclusion, our results suggested that long-term treatment with MG132 attenuates pressureoverload-induced cardiac hypertrophy and improves cardiac function in AAB rats through regulation of ERK1/2 and JNK1 signaling pathways.
Acta Biochimica et Biophysica Sinica 04/2010; 42(4):253-8. · 1.38 Impact Factor
