Xiaohui Zhang

Harbin Medical University, Charbin, Heilongjiang Sheng, China

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Publications (7)20.89 Total impact

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    ABSTRACT: Increased vascular smooth muscle cell (VSMC) proliferation substantially contributes to the pathogenesis of atherosclerosis and intimal hyperplasia after vascular injury. The importance of inflammation in VSMC proliferation is now being recognized. Preventing the inflammatory response is one therapeutic strategy that can be used to inhibit atherosclerosis in the clinic. The present study, using RNA interference and gene transfer techniques, was conducted to investigate the effect of monocyte chemotactic protein-3 (MCP-3) on VSMC proliferation that is a result of TNF-α stimulation, and whether overexpression of the tissue factor pathway inhibitor (TFPI) gene could prevent VSMC proliferation by blocking the MCP-3/CC chemokine receptor 2 (CCR2) pathway. Mouse VSMCs were infected in vitro with recombinant adenoviruses containing either mouse MCP-3-shRNA (Ad-MCP-3-shRNA), the TFPI gene (Ad-TFPI), or the negative control, which was shRNA encoding the sequence for EGFP (Ad-EGFP) or DMEM only. The cells were then stimulated with TNF-α for different time periods on the third day after gene transfer. The data show that VSMC proliferation in the Ad-MCP-3-shRNA and Ad-TFPI groups was markedly decreased using BrdU ELISA and MTT assays; MCP-3-shRNA and TFPI inhibited the expression of MCP-3 and CCR2 after long-term stimulation and inhibited the phosphorylation of ERK1/2 and AKT after short-term stimulation, as shown by ELISA and western blot analysis. This study provides convincing evidence that clarifies the effect of the proinflammatory factor MCP-3 in promoting VSMC proliferation. Our data also show, for the first time, that TFPI has an anti-proliferative role in TNF-α stimulated-VSMCs at least partly by interfering with the MCP-3/CCR2 pathway and then via suppression of the ERK1/2 and PI3K/AKT signaling pathways. We conclude that TFPI gene transfer may be a safe and effective therapeutic tool for treating atherosclerosis and intimal hyperplasia.
    Laboratory Investigation 08/2015; DOI:10.1038/labinvest.2015.106 · 3.68 Impact Factor
  • Wenxiu Liu · Xin Zhang · Meng Zhao · Xiaohui Zhang · Jinyu Chi · Yue Liu · Fang Lin · Yu Fu · Dandan Ma · Xinhua Yin
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    ABSTRACT: Macrophage (MΦ) infiltration during myocardial infarction (MI) amplifies cardiac inflammation and remodeling. We investigated whether activation of the NRLP3 inflammasome by a calcium sensing receptor (CaSR) in MΦ subsets contributes to cardiac remodeling following MI. Infiltrated MΦ exhibited biphasic activation after MI; M1MΦ peaked at MI 3d and decreased until MI 14d, whereas M2MΦ peaked at MI 7d and decreased at MI 14d as shown via immunohistochemistry. IL-1β co-infiltrated with both M1MΦ and M2MΦ; IL-1β exhibited the same infiltrating tendency as M1MΦ, which was detected by immunohistochemistry. Increasing ventricular fibrosis was confirmed by Masson staining. CaSR and NLRP3 inflammasome in the MI group were upregulated in MΦ subsets in myocardium and peritoneal MΦ (p-MΦ) compared with the sham groups which were detected by immunofluorescence and western blotting. CaSR-activated NLRP3 inflammasome played a role in M1MΦ via PLC-IP3 but did not play a role in M2MΦ which were polarized by the THP-1 as shown by western blotting and intracellular calcium measurement. CaSR/NLRP3 inflammasome activation in M1MΦ led to the following effects: upregulated α-sma, MMP-2 and MMP-9, and collagen secretion; and downregulated TIMP-2 in cardiac fibroblasts via IL-1β-IL-1RI, which was detected by coculturing M1MΦ and cardiac fibroblasts. We suggest that the CaSR/NLRP3 inflammasome plays an essential role via the PLC-IP3 pathway in M1MΦ to promote cardiac remodeling post-MI in rats, including accelerated cardiac fibroblast phenotypic transversion, increased collagen and extracellular matrix (ECM) secretion; however, the CaSR/NLRP3 inflammasome does not play a role in this process in M2MΦ. © 2015 S. Karger AG, Basel.
    Cellular Physiology and Biochemistry 04/2015; 35(6):2483-2500. DOI:10.1159/000374048 · 2.88 Impact Factor
  • Xiaohui Zhang · Xiao Ma · Meng Zhao · Bo Zhang · Jinyu Chi · Wenxiu Liu · Wenjia Chen · Yu Fu · Yue Liu · Xinhua Yin
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    ABSTRACT: High concentrations of glucose induce cardiomyocyte apoptosis, and contribute to diabetic cardiomyopathy. Relaxin-2 and relaxin-3 are two members of the relaxin peptide family that are cardioprotective. However, it remains unknown whether relaxin-2 or relaxin-3 can regulate apoptosis in high glucose treated-neonatal rat ventricular myocytes (NRVMs). In cultured NRVMs, 33 mmol/l high glucose (HG) increased apoptosis in a time-dependent manner. HG-increased the protein expression of cleaved caspase-8 and -9, two initiators of the extrinsic and intrinsic pathways of apoptosis, Caspase-3 was attenuated by human recombinant relaxin-2 (H2 relaxin) or relaxin-3 (H3 relaxin), indicating that H2 and H3 relaxin inhibited HG-induced apoptosis. Furthermore, endoplasmic reticulum stress (ERS) markers CHOP and caspase-12 were markedly increased in HG-treated NRVMs, leading to apoptosis; this effect was also effectively attenuated by H2 relaxin or H3 relaxin. Treatment of NRVMs with HG reduced autophagy which cannot be adjusted by H2 relaxin or H3 relaxin. In conclusion, HG-induced apoptosis in NRVMs was mediated, in part, by the activation of the extrinsic and intrinsic pathways of apoptosis and ERS, all inhibited by H2 relaxin or H3 relaxin.
    Biochimie 11/2014; 108. DOI:10.1016/j.biochi.2014.11.004 · 2.96 Impact Factor
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    ABSTRACT: Relaxin-2 has been found to alleviate fibrosis in experimental diabetic cardiomyopathy. In addition, the levels of serum relaxin-3 were increased and correlated with all the component traits of metabolic syndrome. We investigated the levels of plasma relaxin-2 or relaxin-3 and their relationship to component traits in patients with diabetes. We studied 33 newly diagnosed type 2 diabetes patients and 38 age-matched healthy subjects. Blood samples were taken at study entry, and relaxin-3, relaxin-2, fasting blood glucose, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride, serum insulin and hemoglobin A1c (HbA1c) levels were measured. Relaxin-2 levels were significantly lower in patients with diabetes than in controls: the median plasma relaxin-2 concentration was 34.68pg/ml (range, <29.00-50.81pg/ml) in patients with diabetes and 45.80pg/ml (range, <37.42-54.46pg/ml) in controls (p=0.0150). However, no differences in relaxin-3 levels were observed between the diabetes group and controls (p=0.6550). The plasma levels of relaxin-2 or relaxin-3 were not correlated with systolic blood pressure (BP), diastolic BP, total cholesterol, LDL-C, HDL-C, triglyceride, fasting blood glucose, fasting insulin and HbA1c in patients with diabetes. Additionally, there was no correlation between the plasma concentrations of relaxin-2 and relaxin-3 in patients with diabetes (rs=0.225; p=0.208). We conclude that the plasma levels of relaxin-2 in diabetes patients were lower than in controls, however, there are no difference in plasma relaxin-3 concentrations between controls and patients with diabetes. Relaxin-2 or relaxin-3 levels are not related to component traits in patients with diabetes.
    Clinical biochemistry 08/2013; 46(16-17). DOI:10.1016/j.clinbiochem.2013.08.007 · 2.28 Impact Factor
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    ABSTRACT: Cyclosporine (CsA) has become a mainstay for immune suppression of organ transplants. It is known that patients receiving CsA manifest increased growth of aggressive cardiotoxicity. We have demonstrated that CsA induces myocardium cell apoptosis in vivo and vitro. Recently, dishevelled-1 (Dvl-1) protein, which is a cytoplasmic mediator of Wnt/β-catenin signaling, was explored in cardiac diseases. However, whether Dvl-1 is involved in CsA-induced apoptosis remains to be determined. The aim of this study was to explore the role of Dvl-1 in CsA-induced apoptosis in H9c2 cardiomyoblast cells and to investigate the role of the Wnt/β-catenin signaling cascade in this progress. H9c2 cells were treated with CsA in dose and time-dependent manners. We found that the appropriate concentrations and time-points of CsA-induced the expression of Dvl-1 and subsequent up-regulation of β-catenin and c-Myc, which is consistent with previously demonstrated concentrations and time-points when H9c2 cells apoptosis occurred. Then, cells were transfected with small interfering RNA (siRNA) against Dvl-1 and stimulated with previously demonstrated concentration of CsA. Dvl-1 down-regulation decreased the apoptotic rate, caspase-3 activity, and the Bax/Bcl-2 ratio in H9c2 cells treated with CsA. Furthermore, knocking down the expression of Dvl-1 partially suppressed the activity of the Wnt/β-catenin pathway. Moreover, we further deleted the downstream member β-catenin by specific siRNA, and found that CsA-induced the Bax/Bcl-2 ratio and the expression of c-Myc, which were attenuated. Our results are the first to unveil this novel aspect of Dvl-1 signaling. In addition, these data provide insight into the pathogenesis and the therapeutic strategies of CsA-induced myocardial injury.
    Molecular and Cellular Biochemistry 11/2012; 374(1-2). DOI:10.1007/s11010-012-1510-9 · 2.39 Impact Factor
  • Yu Fu · Yong Zhao · Yue Liu · Yejing Zhu · Jinyu Chi · Jing Hu · Xiaohui Zhang · Xinhua Yin
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    ABSTRACT: In our previous study, we have demonstrated that tissue factor pathway inhibitor (TFPI) gene could induce vascular smooth muscle cell (VSMC) apoptosis. This study was conducted to investigate whether the overexpression of the TFPI gene can induce VSMC apoptosis by inhibiting JAK-2/STAT-3 pathway phosphorylation and thereby inhibiting the expression of such downstream targets as the apoptotic protein Bcl-2 and cell cycle protein cyclin D1. The effect of TFPI on the expression of survivin, a central molecule in cell survival, was also investigated. Rat VSMCs were infected with recombinant adenovirus containing either the TFPI (Ad-TFPI) or LacZ (Ad-LacZ) gene or DMEM in vitro. TFPI expression was detected by ELISA. TUNEL staining and electron microscope were carried out to determine the apoptosis of VSMCs. The expression levels of JAK-2, p-JAK-2, STAT-3, p-STAT-3, cyclin D1, Bcl-2 and survivin were examined by western blot analysis. TFPI protein was detected in the TFPI group after gene transfer and the peak expression was at the 3rd day. At the 3rd, 5th and 7th days after gene transfer, the apoptotic rates by TUNEL assay in the TFPI group were 10.91 ± 1.66%, 13.46 ± 1.28% and 17.04 ± 1.95%, respectively, whereas those in the LacZ group were 3.28 ± 0.89%, 4.01 ± 0.72% and 4.89 ± 1.17%, respectively. We observed cell contraction, slight mitochondrial swelling, nuclear pyknosis and apoptotic body formation in TFPI-treated VSMCs using electron microscopy. JAK-2, p-JAK-2, STAT-3, p-STAT-3, cyclin D1 and Bcl-2, which are all involved in the JAK-2/STAT-3 pathway, were detected in the VSMCs on the 3rd, 5th and 7th days after gene transfer, which is consistent with previously demonstrated time points when VSMCs apoptosis occurred. The expression levels of p-JAK-2, p-STAT-3, cyclin D1 and Bcl-2 were significantly decreased over time in the TFPI group (each P<0.05) but not in the Ad-LacZ and DMEM groups. However, this attenuation of expression was not observed for JAK-2 and STAT-3 in any of the groups at any time points after gene transfer (each P>0.05). The expression level of survivin in the TFPI group also weakened significantly over time compared with the levels in the Ad-LacZ and DMEM groups (each P<0.05) at the 3rd, 5th and 7th days after gene transfer. The results demonstrated that TFPI played an apoptosis-inducing role in VSMCs in a manner that involves both the suppression of JAK-2/STAT-3 pathway phosphorylation and the down-regulation of survivin. Our data show for the first time that targeting the JAK-2/STAT-3 pathway and survivin by overexpressing TFPI may be a new avenue for the treatment of restenosis.
    Cellular Signalling 06/2012; 24(10):1909-17. DOI:10.1016/j.cellsig.2012.06.001 · 4.32 Impact Factor
  • Jinyu Chi · Yejing Zhu · Yu Fu · Yue Liu · Xiaohui Zhang · Lei Han · Xinhua Yin · Dechao Zhao
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    ABSTRACT: The cardiotoxicity of cyclosporine A (CsA) limits its clinical application in extensive and long-term therapies. Our group has shown that CsA induces myocardium cell apoptosis in vivo and increases calcium-sensing receptor (CaSR) expression. However, its molecular mechanism remains unknown. The purpose of this study was to determine whether CaSR plays an essential role in CsA-induced apoptosis in H9c2 cells and to investigate the role of the mitogen-activated protein kinase (MAPK) signaling cascade in this process. H9c2 cells were treated with CsA in a dose-dependent manner, and decreased Bcl-2 expression, increased Bax expression, and caspase-3 activation were observed. In a time-dependent manner, CsA increased CaSR expression, activated the extracellularly regulated kinase (ERK) and p38 MAPK pathways, and inactivated the c-Jun N-terminal kinase (JNK) MAPK signaling pathway. When H9c2 cardiomyoblast cells pretreated with gadolinium chloride (GdCl(3)), a CaSR activator, were treated with CsA, decreased phosphorylation of ERK1/2, increased phosphorylation of p38, decreased Bcl-2 expression, increased Bax expression, and activated caspase-3 were observed. Cells pretreated with the CaSR inhibitor NPS2390 inhibited this process. Furthermore, the MEK1/2 inhibitor U0126 and the p38 MAPK inhibitor SB203580 markedly blocked the effect of CsA on cell apoptosis, apoptotic-related protein expression, and caspase-3 activation. These findings showed that CsA induced apoptosis in H9c2 cells in vitro, and CaSR mediated the degradation of ERK MAPK and the upregulation of the p38 MAPK pathway involved in CsA-induced H9c2 cardiomyoblast cell apoptosis.
    Molecular and Cellular Biochemistry 06/2012; 367(1-2):227-36. DOI:10.1007/s11010-012-1336-5 · 2.39 Impact Factor