Yinchuan Xu

Zhejiang University, Hang-hsien, Zhejiang Sheng, China

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Publications (13)63.71 Total impact

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    ABSTRACT: Heparanase plays important roles in tumor angiogenesis. Our previous study demonstrated that hypoxic preconditioning (HPC) enhanced the angiogenic and therapeutic effects of MSCs, effects that were paralleled by enhanced heparanase expression. The present study was designed to elucidate the role of heparanase in the improved therapeutic properties of HPC-MSCs and to explore underlying mechanisms using an ischemic rat hindlimb model. MSCs transfected with heparanase (MSC(hpa) ) or empty vector (MSC(null) ) were delivered by intramuscular injections to ischemic hindlimbs. Hindlimbs that received MSC(hpa) recovered blood flow more rapidly at 7 days and acquired higher capillary density at 14 days compared with MSC(null) . Conditioned medium from MSC(hpa) increased endothelial cell migration and promoted greater tube formation relative to that from the MSC(null) groups. Vascular endothelial growth factor receptor 2 (VEGFR2, Flk-1) and its downstream signaling pathway (p38MAPK/HSP27) were significantly increased in HUVECs after treatment with MSC(hpa) conditioned medium. Each of these responses were decreased by co-cultured with MSC(hpa-KD) conditioned medium. MSC(hpa) conditioned medium activated hypoxia-inducible factor-2α (HIF-2α) and increased in parallel the transcript level of Flk-1 as determined by ChIP-PCR and luciferase assays. Analyses of integrin expression revealed an important role for integrin β1 in the regulation of HIF2α. All angiogenic effects of MSC(hpa) conditioned medium were abolished by knockdown of intergrin β1, HIF-2α and Flk-1 in HUVECs with selective shRNAs. These findings identify heparanse as a key regulator of angiogenesis by MSCs. We propose a novel pathway wherein heparanse sequentially activates integrin β1, HIF-2α, Flk-1 and p38MAPK/HSP27 with corresponding enhancement of angiogenesis. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 03/2015; 33(6). DOI:10.1002/stem.1995 · 6.52 Impact Factor
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    ABSTRACT: Renin cleavage of angiotensinogen (AGT) releases angiotensin I (AngI) in the initial step of producing all angiotensin peptides. It has been suggested recently that redox regulation of a disulfide bond in AGT involving Cys18-Cys137 may be important to its renin cleavage efficiency in vivo. The purpose of this study was to test this prediction in a mouse model by comparing AngII production and AngII-dependent functions in mice expressing wild-type AGT versus a mutated form of AGT lacking the disulfide bond. Wild-type (hepAGT+/+) and hepatocyte-specific AGT-deficient (hepAGT-/-) littermates were developed in an low-density lipoprotein receptor -/- background. hepAGT+/+ mice were injected intraperitoneally with adeno-associated viral (AAV) vector containing a null insert. hepAGT-/- mice were injected with AAV containing a null insert, wild-type AGT or Cys18Ser and Cys137Ser mutated AGT. Two weeks after AAV injection, mice were fed a Western diet for 12 weeks. Administration of AAV containing either form of AGT led to similar plasma AGT concentrations in hepAGT-/- mice. High plasma renin concentrations in hepAGT-/- mice were suppressed equally by both forms of AGT, which were accompanied by comparable increases of plasma AngII concentrations similar to hepAGT+/+ mice. AAV-driven expression of both forms of AGT led to equivalent increases of systolic blood pressure and augmentation of atherosclerotic lesion size in hepAGT-/- mice. These measurements were comparable to systolic blood pressure and atherosclerotic lesions in hepAGT+/+ mice. These data indicate that the Cys18-Cys137 disulfide bond in AGT is dispensable for AngII production and AngII-dependent functions in mice. © 2015 American Heart Association, Inc.
    Hypertension 02/2015; 65(4). DOI:10.1161/HYPERTENSIONAHA.115.05166 · 6.48 Impact Factor
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    ABSTRACT: Background Previous studies demonstrated that biological aging exerts a negative effect on the therapeutic effects of mesenchymal stem cells (MSCs)-based therapy. Here, using a rat myocardial infarction (MI) model, we tested the hypothesis that SIRT1 may ameliorate the phenotype and improve the function of aged MSCs and hence enhance the efficacy of aged MSCs-based therapy. Methods Sixty female rats experienced left anterior descending coronary artery ligation and were randomly assigned to receiving intramyocardial injection of cell culture medium (DMEM group), SIRT1 overexpression vector treated-aged MSCs (SIRT1-aged MSC group) obtained from aged male SD rats or empty vector treated-aged MSCs (vector-aged MSC group). Another twenty sham operated rats underwent open-chest surgery without coronary ligation and any other intervention served as controls. Results SIRT1-aged MSCs group exhibited enhanced blood vessel density in the border zone of MI hearts, which was associated with reduced cardiac remodeling, leading to an improved cardiac performance. Consistent with the in vivo data, our in vitro experiments also demonstrated that SIRT1 overexpression ameliorated aged MSCs senescent phenotype and recapitulated the pro-angiogenesis property of MSCs and conferred the anti-stress response capabilities, as indicated by increases in pro-angiogenic factors, angiopoietin 1 (Ang1) and basic fibroblast growth factor (bFGF), expressions and a decrease in anti-angiogenic factor thrombospondin-1 (TBS1) at mRNA levels, and increases in Bcl-2/Bax ratio at protein level. Conclusions Up-regulating SIRT1 expression could enhance the efficacy of aged MSCs-based therapy for MI which is related to the amelioration of senescent phenotype and hence improved biological function of aged MSCs.
    The Journal of Heart and Lung Transplantation 10/2014; 33(10). DOI:10.1016/j.healun.2014.05.008 · 6.65 Impact Factor
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    ABSTRACT: Hypoxia preconditioning enhances the therapeutic effect of mesenchymal stem cells (MSCs). However, the mechanism underlying hypoxia-induced augmentation of the protective effect of MSCs on myocardial infarction (MI) is poorly understood. We show that hypoxia-enhanced survival, mobility, and protection of co-cultured cardiomyocytes were paralleled by increased expression of leptin and cell surface receptor CXCR4. The enhanced activities were abolished by either knockdown of leptin with a selective shRNA or by genetic deficiency of leptin or its receptor in MSCs derived respectively from ob/ob or db/db mice. To characterize the role of leptin in the regulation of MSC functions by hypoxia and its possible contribution to enhanced therapeutic efficacy, cell therapy using MSCs derived from wild type, ob/ob, or db/db mice was implemented in mouse models of acute MI. Augmented protection by hypoxia pretreatment was only seen with MSCs from wild type mice. Parameters that were differentially affected by hypoxia pretreatment included MSC engraftment, c-Kit+ cell recruitment to the infarct, vascular density, infarct size and long-term contractile function. These data show that leptin signaling is an early and essential step for the enhanced survival, chemotaxis, and therapeutic properties of MSCs conferred by pre-culture under hypoxia. Leptin may play a physiological role in priming MSCs resident in the bone marrow endosteum for optimal response to systemic signaling molecules and subsequent tissue repair. Stem Cells 2014
    Stem Cells 10/2014; 32(10). DOI:10.1002/stem.1784 · 6.52 Impact Factor
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    ABSTRACT: Aims Activation of cardiac fibroblasts into myofibroblasts constitutes a key step in cardiac remodeling after myocardial infarction (MI), due to interstitial fibrosis. Mesenchymal stem cells (MSCs) have been shown to improve post-MI remodeling an effect that is enhanced by hypoxia preconditioning (HPC). Leptin has been shown to promote cardiac fibrosis. The expression of leptin is significantly increased in MSCs after HPC but it is unknown whether leptin contributes to MSC therapy or the fibrosis process. The objective of this study was to determine whether leptin secreted from MSCs modulates cardiac fibrosis. Methods Cardiac fibroblast (CF) activation was induced by hypoxia (0.5% O2). The effects of MSCs on fibroblast activation were analyzed by co-culturing MSCs with CFs, and detecting the expression of α-SMA, SM22α, and collagen IαI in CFs by western blot, immunofluorescence and Sirius red staining. In vivo MSCs antifibrotic effects on left ventricular remodeling were investigated using an acute MI model involving permanent ligation of the left anterior descending coronary artery. Results Co-cultured MSCs decreased fibroblast activation and HPC enhanced the effects. Leptin deficit MSCs from Ob/Ob mice did not decrease fibroblast activation. Consistent with this, H-MSCs significantly inhibited cardiac fibrosis after MI and mediated decreased expression of TGF-β/Smad2 and MRTF-A in CFs. These effects were again absent in leptin-deficient MSCs. Conclusion Our data demonstrate that activation of cardiac fibroblast was inhibited by MSCs in a manner that was leptin-dependent. The mechanism may involve blocking TGF-β/Smad2 and MRTF-A signal pathways.
    PLoS ONE 08/2014; 9(8):e103587. DOI:10.1371/journal.pone.0103587 · 3.23 Impact Factor
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    ABSTRACT: Mesenchymal stem cells (MSCs) senescence is an age-related process that impairs the capacity for tissue repair and compromises the clinical use of autologous MSCs for tissue regeneration. Here, we describe the effects of SIRT1, a NAD(+)-dependent deacetylase, on age-related MSCs senescence. Knockdown of SIRT1 in young MSCs induced cellular senescence and inhibited cell proliferation whereas overexpression of SIRT1 in aged MSCs reversed the senescence phenotype and stimulated cell proliferation. These results suggest that SIRT1 plays a key role in modulating age-induced MSCs senescence. Aging-related proteins, P16 and P21 may be downstream effectors of the SIRT1-mediated anti-aging effects. SIRT1 protected MSCs from age-related DNA damage, induced telomerase reverse transcriptase (TERT) expression and enhanced telomerase activity but did not affect telomere length. SIRT1 positively regulated the expression of tripeptidyl peptidase 1 (TPP1), a component of the shelterin pathway that protects chromosome ends from DNA damage. Together, the results demonstrate that SIRT1 quenches age-related MSCs senescence by mechanisms that include enhanced TPP1 expression, increased telomerase activity and reduced DNA damage.
    Frontiers in Aging Neuroscience 06/2014; 6:103. DOI:10.3389/fnagi.2014.00103 · 4.00 Impact Factor
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    ABSTRACT: The therapeutic efficiency of bone marrow mononuclear cells (BMMNCs) autologous transplantation for myocardial infarction (MI) remains low. Here we developed a novel strategy to improve cardiac repair by preconditioning BMMNCs via angiotensin II type 2 receptor (AT2R) stimulation. Acute MI in rats led to a significant increase of AT2R expression in BMMNCs. Preconditioning of BMMNCs via AT2R stimulation directly with an AT2R agonist CGP42112A or indirectly with angiotensin II plus AT1R antagonist valsartan led to ERK activation and increased eNOS expression as well as subsequent nitric oxide generation, ultimately improved cardiomyocyte protection in vitro as measured by co-culture approach. Intramyocardial transplantation of BMMNCs preconditioned via AT2R stimulation improved survival of transplanted cells in ischemic region of heart tissue and reduced cardiomyocyte apoptosis and inflammation at 3 days after MI. At 4 weeks after transplantation, compared to DMEM and non-preconditioned BMMNCs group, AT2R stimulated BMMNCs group showed enhanced vessel density in peri-infarct region and attenuated infarct size, leading to global heart function improvement. Preconditioning of BMMNCs via AT2R stimulation exerts protective effect against MI. Stimulation of AT2R in BMMNCs may provide a new strategy to improving therapeutic efficiency of stem cells for post MI cardiac repair.
    PLoS ONE 12/2013; 8(12):e82997. DOI:10.1371/journal.pone.0082997 · 3.23 Impact Factor

  • International journal of cardiology 07/2013; 168(4). DOI:10.1016/j.ijcard.2013.06.087 · 4.04 Impact Factor
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    ABSTRACT: Human endometrial stem cells (EnSCs) have the potential to be 'off the shelf' clinical reagents for the treatment of heart failure. Here, using an immunocompetent rat model of myocardial infarction (MI), we provide evidence that the functional benefits of EnSC transplantation are principally and possibly exclusively through a paracrine effect. Human EnSCs were delivered by intramyocardial injection into rats 30 min. after coronary ligation. EnSC therapy significantly preserved viable myocardium in the infarct zone and improved cardiac function at 28 days. Despite increased viable myocardium and vascular density, there was scant evidence of differentiation of EnSCs into any cardiovascular cell type. Cultured human EnSCs expressed a distinctive profile of cytokines that enhanced the survival, proliferation and function of endothelial cells in vitro. When injected into the peri-infarct zone, human EnSCs activated AKT, ERK1/2 and STAT3 and inhibited the p38 signalling pathway. EnSC therapy decreased apoptosis and promoted cell proliferation and c-kit+ cell recruitment in vivo. Myocardial protection and enhanced post-infarction regeneration by EnSCs is mediated primarily by paracrine effects conferred by secreted cytokines that activate survival pathways and recruit endogenous progenitor stem cells. Menstrual blood provides a potentially limitless source of biologically competent 'off the shelf' EnSCs for allogeneic myocardial regenerative medicine.
    Journal of Cellular and Molecular Medicine 07/2013; 17(10). DOI:10.1111/jcmm.12100 · 4.01 Impact Factor

  • International journal of cardiology 04/2013; 168(2). DOI:10.1016/j.ijcard.2013.03.126 · 4.04 Impact Factor
  • Yinchuan Xu · Jian-an Wang ·

    23rd Great Wall International Congress of Cardiology/Asia Pacific Heart; 10/2012
  • Zhi Jiang · Xinyang Hu · Yinchuan Xu · Rongrong Wu · Jian An Wang ·

    Heart (British Cardiac Society) 10/2011; 97(Suppl 3):A30-A31. DOI:10.1136/heartjnl-2011-300867.88 · 5.60 Impact Factor
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    ABSTRACT: Abdominal aortic aneurysm (AAA) is a chronic vascular disease characterized by medial degradation and inflammation. No medical approaches have been validated for treating AAA, and therapeutic options are limited to regular surveillance leading to surgical intervention. This study aimed to investigate whether administration of Chinese red yeast rice (Monascus purpureus; RYR) suppressed angiotensin II (AngII)-induced AAA and atherosclerosis. Apolipoprotein E-deficient male mice fed a normal diet were administered either RYR extract (200 mg/kg/day) or vehicle by gavage for 1 week before initiating AngII infusion (1000 ng/kg/min) via subcutaneous osmotic pumps for 28 days. Red yeast rice extract administration significantly suppressed AngII-induced expansion of suprarenal diameter and area (P<.05). Furthermore, RYR extract significantly reduced atherosclerotic lesion areas in both the intima of aortic arches and cross sections of aortic roots (P<.05). These effects were associated with reductions of serum total cholesterol, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, matrix metalloproteinase (MMP) 2 and increases of serum macrophage migration inhibitory factor, but no changes in serum interleukin (IL) 1α, IL-6, monocyte chemoattractant protein 1, MMP-9 and expression of MMP-2 and MMP-9 in aortic walls. This study demonstrated that RYR extract administration suppressed AngII-induced AAA and atherosclerosis associated with regulating inflammation responses independent of lipid-lowering effects. Red yeast rice may have preventive potential for patients with AAA.
    The Journal of nutritional biochemistry 07/2011; 23(6):549-56. DOI:10.1016/j.jnutbio.2011.02.011 · 3.79 Impact Factor

Publication Stats

37 Citations
63.71 Total Impact Points


  • 2011-2014
    • Zhejiang University
      Hang-hsien, Zhejiang Sheng, China
  • 2011-2013
    • Zhejiang Medical University
      • Department of Cardiology
      Hang-hsien, Zhejiang Sheng, China