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Bo Li, Zhe Dong,
Hui Liu,
Yan-Fei Xia,
Xiao-Man Liu,
Bei-Bei Luo,
Wen-Ke Wang,
Bin Li,
Fei Gao,
Cheng Zhang,
Ming-Xiang Zhang,
Yun Zhang,
Feng-Shuang An
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ABSTRACT: OBJECTIVES: Although lipoprotein-associated phospholipase A2 (Lp-PLA2) has been regarded as a biomarker and a causative agent for acute coronary events recently, the mechanism of the regulation of Lp-PLA2 has not been fully elucidated yet. This study was aimed to investigate the influence of serum amyloid A (SAA) on the expression of Lp-PLA2 in THP-1 cells and ApoE-deficient (ApoE(-/-)) mice. METHODS: THP-1 cells were stimulated by SAA and the mRNA and protein expression of Lp-PLA2 was detected. ApoE(-/-) mice were intravenously injected with murine SAA1 lentivirus. Formyl peptide receptor like-1 (FPRL1) agonist (WKYMVm) and inhibitor (WRW(4)), mitogen-activated protein kinases (MAPKs) inhibitors, and peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and inhibitor were used to investigate the mechanism of regulation of Lp-PLA2. RESULTS: Recombinant SAA up-regulated Lp-PLA2 expression in a dose and time-dependent manner in THP-1 cells. Immunohistochemical analysis of aortic root of ApoE(-/-) mice also demonstrated that the expression of Lp-PLA2 was up-regulated significantly with SAA treatment. WRW(4) decreased SAA-induced Lp-PLA2 production; while WKYMVm could induce Lp-PLA2 expression. ERK1/2, JNK1/2, and p38 inhibition reduced SAA-induced Lp-PLA2 production. Furthermore, the results suggested the activation of PPAR-γ played a crucial role in this process. CONCLUSION: These results demonstrate that SAA up-regulates Lp-PLA2 production significantly via a FPRL1/MAPKs./PPAR-γ signaling pathway.
Atherosclerosis 04/2013; · 3.79 Impact Factor
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ABSTRACT: Abstract Background: The nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome is a multiprotein complex consisting of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1. In peripheral blood mononuclear cells (PBMCs), NLRP3 can activate interleukin-1β (IL-1β), important in the chronic inflammatory process of idiopathic dilated cardiomyopathy (IDCM). Therefore, the NLRP3 inflammasome in PBMCs may be involved in the pathogenesis of IDCM. We evaluated the association of circulating levels of NLRP3 inflammasome and cardiac function in patients with IDCM and 6-month rehospitalization. Methods: We enrolled 54 patients with IDCM and 20 healthy volunteers and analyzed left ventricle ejection fraction (LVEF), electrocardiography findings and circulating levels of NLRP3, ASC, caspase-1, IL-1β, N terminal-pro type B natriuretic peptide (NT-pro BNP) and blood values. Patients were followed up for 6 months. Results: On admission and discharge, the circulating levels of NLRP3, ASC, caspase-1 and IL-1β were higher in IDCM patients than healthy controls (all p<0.05). In patients, NLRP3 mRNA level was associated with LVEF, NT-pro BNP level and monocyte count (all p<0.05). LVEF at admission and mRNA levels of NLRP3 and IL-1β at discharge were independent risk factors of 6-month rehospitalization for patients. High NLRP3 mRNA level was associated with cumulative rehospitalization rate (p<0.05). Conclusions: NLRP3 level in PBMCs may be associated with cardiac function and rehospitalization in IDCM patients.
Clinical Chemistry and Laboratory Medicine 02/2013; · 2.15 Impact Factor
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ABSTRACT: Myocarditis is an acute inflammatory disease of the heart and is often a precursor of dilated cardiomyopathy. Experimental autoimmune myocarditis (EAM) has been used as a model for human myocarditis. The purpose of this study was to investigate the therapeutic role of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, rosuvastatin, on the development of EAM.
Experimental autoimmune myocarditis was induced in BALB/c mice by immunization with murine cardiac α-myosin heavy chain (MyHc-α(614-629) [Ac-SLKLMATLFSTYASAD-OH]). High-dose (10 mg/kg/day) or low-dose (1 mg/kg/day) rosuvastatin or vehicle was administered orally by gastric gavage to mice with EAM from day 0 to day 21 after immunization. On day 21 after immunization, echocardiography was carried out and the severity of myocarditis was detected by histopathological evaluation. Levels of serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured by ELISA. Histopathology was performed using haematoxylin and eosin. With apoptosis examined by Tunel, the expression of active caspase-3 in myocardium was investigated by immunohistochemistry.
Rosuvastatin attenuated the histopathological severity of myocarditis. Cardiac function was improved in the two rosuvastatin-treated groups compared to the non-treated EAM group (LVFS: high-dose rosuvastatin group [group H], 0.38 ± 0.10%; low-dose rosuvastatin group [group L], 0.34 ± 0.06%; non-treated EAM group [group N], 0.29 ± 0.07%. LVEF: group H, 0.80 ± 0.09%; group L, 0.71 ± 0.07%; group N, 0.68 ± 0.07%). Furthermore, treatment with rosuvastatin decreased the expression levels of TNF-α (group H, 65.19 ± 7.06 pg/ml; group L, 108.20 ± 5.28 pg/ml; group N, 239.34 ± 11.65 pg/ml) and IL-6 (group H, 14.33 ± 2.15 pg/ml; group L, 19.67 ± 3.04 pg/ml; group N, 40.39 ± 7.17 pg/ml). The rates of expression of active Caspase-3 and myocardial apoptosis were positively correlated with the scores for myocardial pathology.
These results demonstrate that administration of rosuvastatin can ameliorate EAM progression, inhibit apoptosis of cardiomyocytes, and preserve cardiac output, and they also suggest rosuvastatin may be a promising novel therapeutic strategy for the clinical treatment of myocarditis.
Cardiovascular Drugs and Therapy 03/2012; 26(2):121-30. · 3.13 Impact Factor
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ABSTRACT: Several clinical trials have reported inconsistent findings for the effects of rosuvastatin (RSV) and atorvastatin (ATV) on renal function. The aim of this meta-analysis was to investigate the effects of these 2 statins on glomerular filtration rate (GFR) and proteinuria respectively, and determine which is better.
PubMed, CENTRAL, Web of Knowledge, and ClinicalTrials.gov website were searched for randomized controlled trials. Eligible studies reported GFR and/or proteinuria during treatment with RSV or ATV compared with control (placebo, no statins, or usual care), or RSV compared with ATV head to head. Trials that enrolled dialysis participants and teenagers were excluded. Statistical heterogeneity was assessed using the I(2) statistic, and pooled results using the random-effects model. The standardized mean differences (SMD) and ratio of means (ROM) were measured, respectively, to analyze GFR and proteinuria. Sixteen trials with a total number of 24,278 participants were identified. Compared with control, changes in the SMD of GFR were 0.04 (95% confidence interval [CI]: 0.01-0.07) and 0.59 (95%CI: 0.12-1.06) for RSV and ATV, respectively. The ROMs of proteinuria were 0.59 (95%CI: 0.46-0.74) for RSV vs. the control group, and 1.23 (95%CI: 1.05-1.43) in the head-to-head comparison.
Both RSV and ATV improve GFR, and ATV seems to be more effective in reducing proteinuria. The validity and clinical significance require high-quality intensive studies with composite clinic endpoints of kidney and death.
Circulation Journal 03/2012; 76(5):1259-66. · 3.77 Impact Factor
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ABSTRACT: Although serum amyloid A (SAA) is an excellent marker for coronary artery disease, its direct effect on atherogenesis in vivo is obscure. In this study we investigated the direct effect of SAA on promoting the formation of atherosclerosis in apolipoprotein E-deficient (ApoE⁻/⁻) mice. Murine SAA lentivirus was constructed and injected into ApoE⁻/⁻ mice intravenously. Then, experimental mice were fed a chow diet (5% fat and no added cholesterol) for 14 wks. The aortic atherosclerotic lesion area was larger with than without SAA treatment. With increased SAA levels, the plasma levels of interleukin-6 and tumor necrosis factor-α were significantly increased. Macrophage infiltration in atherosclerotic regions was enhanced with SAA treatment. A migration assay revealed prominent dose-dependent chemotaxis of SAA to macrophages. Furthermore, the expression of monocyte chemotactic protein-1 and vascular cell adhesion molecule-1 (VCAM-1) was upregulated significantly with SAA treatment. SAA-induced VCAM-1 production was detected in human aortic endothelial cells in vitro. Thus, an increase in plasma SAA directly accelerates the progression of atherosclerosis in ApoE⁻/⁻ mice. SAA is not only a risk marker for atherosclerosis but also an active participant in atherogenesis.
Molecular Medicine 09/2011; 17(11-12):1357-64. · 3.76 Impact Factor
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ABSTRACT: Serum amyloid A (SAA) is regarded as an important acute phase protein in coronary artery diseases. However, its involvement in the immune response of atherosclerosis is poorly understood. The present study was designed to investigate the influence of SAA on the secretion of long pentraxin 3 (PTX3), a key component of innate immunity, in human aortic endothelial cells (HAECs). Our study revealed that recombinant SAA up-regulated PTX3 production in a remarkable dose- and time-dependent manner and the activation of formyl peptide receptor-like 1 (FPRL1) was crucial for SAA-induced expression of PTX3 in HAECs. Meanwhile, SAA-induced PTX3 production could be significantly down-regulated by using the specific siRNA sequences for Jun N-terminal kinases (JNK). Furthermore, the activation of activator protein-1 (AP-1) was necessary for the up-regulation of PTX3 expression. We also found that the activation of nuclear factor-kappa B (NF-κB) played an important role in this process. Our findings demonstrate that SAA up-regulates PTX3 production via FPRL1 significantly, and thus, contributes to the inflammatory pathogenesis of atherosclerosis.
Journal of Cellular Biochemistry 04/2011; 112(8):2097-105. · 2.87 Impact Factor
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ABSTRACT: Recently studies indicated that valsartan could prevent the progression of heart failure caused by diabetic cardiomyopathy (DCM), while the mechanisms were still poorly understood. The present study was designed to investigate whether valsartan could reduce the endoplasmic reticulum (ER) stress and DCM-induced cardiac remodeling. Our data has shown that valsartan can ameliorate ER stress-induced cardiac remodeling and myocardial apoptosis in DCM rats. By using of immunofluorescence and RT-PCR, valsartan has been found to play a protective role via down-regulating the expression of transcriptional induction of C/EBP homologous protein (CHOP) and p53 upregulated modulator of apoptosis (Puma), two crucial factors known to be implicated in the ER stress-induced myocardial apoptosis. And the expression level of Puma was closely related to CHOP. Thus, our experiment strongly suggests that the administration of valsartan can ameliorate the ER stress through blocking the activation of CHOP/Puma signaling pathway, which provides a new insight into the potential molecular mechanism of cardiomyocyte apoptosis.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 02/2011; 42(5):496-502. · 2.61 Impact Factor
