Zhou-Yan Bian

Wuhan University, Wu-han-shih, Hubei, China

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Publications (30)131.89 Total impact

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    ABSTRACT: Icariin, the major active component isolated from plants of the Epimedium family, has been reported to have potential protective effects on the cardiovascular system. However, it is not known whether icariin has a direct effect on angiotensin II (Ang II)-induced cardiomyocyte enlargement and apoptosis. In the present study, embryonic rat heart-derived H9c2 cells were stimulated by Ang II, with or without icariin administration. Icariin treatment was found to attenuate the Ang II-induced increase in mRNA expression levels of hypertrophic markers, including atrial natriuretic peptide and B-type natriuretic peptide, in a concentration-dependent manner. The cell surface area of Ang II-treated H9c2 cells also decreased with icariin administration. Furthermore, icariin repressed Ang II-induced cell apoptosis and protein expression levels of Bax and cleaved-caspase 3, while the expression of Bcl-2 was increased by icariin. In addition, 2',7'-dichlorofluorescein diacetate incubation revealed that icariin inhibited the production of intracellular reactive oxygen species (ROS), which were stimulated by Ang II. Phosphorylation of c-Jun N-terminal kinase (JNK) and p38 in Ang II-treated H9c2 cells was blocked by icariin. Therefore, the results of the present study indicated that icariin protected H9c2 cardiomyocytes from Ang II-induced hypertrophy and apoptosis by inhibiting the ROS-dependent JNK and p38 pathways.
    Experimental and therapeutic medicine 05/2014; 7(5):1116-1122. · 0.34 Impact Factor
  • International journal of cardiology 04/2014; · 6.18 Impact Factor
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    ABSTRACT: Dickkopf-3 (DKK3), a secreted protein in the Dickkopf family, is expressed in various tissues, including the heart, and has been shown to play an important role in tissue development. However, the biological function of DKK3 in the heart remains largely unexplored. This study aimed to examine the role of DKK3 in pathological cardiac hypertrophy.Methods and ResultsWe performed gain-of-function and loss-of-function studies using DKK3 cardiac-specific transgenic mice and DKK3 knockout mice (C57BL/6 J background). Cardiac hypertrophy was induced by aortic banding. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. Our results demonstrated that the loss of DKK3 exaggerated pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction, whereas the overexpression of DKK3 protected the heart against pressure overload-induced cardiac remodeling. These beneficial effects were associated with the inhibition of the ASK1-JNK/p38 (apoptosis signal-regulating kinase 1-c-Jun N-terminal kinase/p38) signaling cascade. Parallel in vitro experiments confirmed these in vivo observations. Co-immunoprecipitation experiments suggested that physical interactions occurred between DKK3 and ASK1. Moreover, rescue experiments indicated that in DKK3 transgenic mice, the activation of ASK1 using a cardiac specific conditional ASK1 transgene reduced the functionality of DKK3 in response to pressure overload; furthermore, the inactivation of ASK1 by dominant-negative ASK1 rescued pressure overload-induced cardiac abnormalities in DKK3 knockout mice. Taken together, our findings indicate that DKK3 acts as a cardioprotective regulator of pathological cardiac hypertrophy and that this function largely occurs via the regulation of ASK1-JNK/p38 signaling.
    Cardiovascular research 01/2014; · 5.80 Impact Factor
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    ABSTRACT: Signal regulatory protein-α (SIRPA/SIRPα) is a transmembrane protein that is expressed in various tissues, including the heart. Previous studies have demonstrated that SIRPA is involved in multiple biological processes, including macrophage multinucleation, skeletal muscle differentiation, neuronal survival, protection against diabetes mellitus, and negative regulation of immune cells. However, the role of SIRPA in cardiac hypertrophy remains unknown. To examine the role of SIRPA in pathological cardiac hypertrophy, we used SIRPA knockout mice and transgenic mice that overexpressed mouse SIRPA in the heart. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. We observed downregulation of SIRPA expression in dilated cardiomyopathy human hearts and in animal hearts after aortic banding surgery. Accordingly, SIRPA(-/-) mice displayed augmented cardiac hypertrophy, which was accompanied by increased cardiac fibrosis and reduced contractile function, as compared with SIRPA(+/+) mice 4 weeks after aortic banding. In contrast, transgenic mice with the cardiac-specific SIRPA overexpression exhibited the opposite phenotype in response to pressure overload. Likewise, SIRPA protected against angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we revealed that SIRPA-mediated protection during cardiac hypertrophy involved inhibition of the Toll-like receptor 4/nuclear factor-κB signaling axis. Furthermore, we demonstrated that the disruption of Toll-like receptor 4 rescued the adverse effects of SIRPA deficiency on pressure overload-triggered cardiac remodeling. Thus, our results identify that SIRPA plays a protective role in cardiac hypertrophy through negative regulation of the Toll-like receptor 4/nuclear factor-κB pathway.
    Hypertension 10/2013; · 6.87 Impact Factor
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    ABSTRACT: Nucleotide-binding oligomerization domain-2 (NOD2, also designated CARD15), a member of the NOD-leucine-rich repeat (LRR) protein family (also called the CATERPILLAR family), is upregulated in atheroma lesions and has an important role in regulating the intracellular recognition of bacterial components by immune cells. However, the effect of NOD2 on cardiac hypertrophy induced by a pathological stimulus has not been determined. Here, we investigated the effects of NOD2 deficiency on cardiac hypertrophy induced by aortic banding (AB) in mice. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. NOD2 expression was upregulated in cardiomyocytes after aortic banding surgery in wild-type (WT) mice. NOD2 deficiency promoted cardiac hypertrophy and fibrosis 4 weeks after AB. Further, the enhanced activation of TLR4 and the MAPKs, NF-κB and TGF-β/Smad pathways were found in NOD2-knockout (KO) mice compared with WT mice. Our results suggest that NOD2 attenuates cardiac hypertrophy and fibrosis via regulation of multiple pathways.Laboratory Investigation advance online publication, 19 August 2013; doi:10.1038/labinvest.2013.99.
    Laboratory Investigation 08/2013; · 3.96 Impact Factor
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    ABSTRACT: Puerarin is the most abundant isoflavonoid in kudzu root. It has been used to treat angina pectoris and myocardial infarction clinically. However, little is known about the effect of puerarin on cardiac hypertrophy. Aortic banding (AB) was performed to induce cardiac hypertrophy in mice. Puerarin premixed in diets was administered to mice after one week of AB. Echocardiography and catheter-based measurements of hemodynamic parameters were performed at 7 weeks after starting puerarin treatment (8 weeks post-surgery). The extent of cardiac hypertrophy was also evaluated by pathological and molecular analyses of heart samples. Cardiomyocyte apoptosis was assessed by measuring Bax and Bcl-2 protein expression and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. In addition, the inhibitory effect of puerarin (1μM, 5μM, 10μM, 20μM, 40μM) on mRNA expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in Ang II (1μM)-stimulated H9c2 cells was investigated using quantitative real-time reverse transcription-polymerase chain reaction. Echocardiography and catheter-based measurements of hemodynamic parameters at 7 weeks revealed the amelioration of systolic and diastolic abnormalities. Puerarin also decreased cardiac fibrosis in AB mice. Moreover, the beneficial effect of puerarin was associated with the normalization in gene expression of hypertrophic and fibrotic markers. Further studies showed that pressure overload significantly induced the activation of phosphoinositide 3-kinase (PI3K)/Akt signaling and c-Jun N-terminal kinase (JNK) signaling, which was blocked by puerarin treatment. Cardiomyocyte apoptosis and induction of Bax in response to AB were suppressed by puerarin. Furthermore, the increased mRNA expression of ANP and BNP induced by Ang II (1μM) was restrained to a different extent by different concentrations of puerarin. Puerarin may have an ability to retard the progression of cardiac hypertrophy and apoptosis which is probably mediated by the blockade of PI3K/Akt and JNK signaling pathways.
    Journal of Cardiology 07/2013; · 2.30 Impact Factor
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    ABSTRACT: To evaluate the prognostic value of late gadolinium enhancement (LGE) in dilated cardiomyopathy (DCM) patients. We searched PubMed, MEDLINE, the Cochrane library and EMBASE databases from September to December 2012 in the Renmin Hospital of Wuhan University, Wuhan, China for studies of LGE in DCM patients. We extracted the clinical outcomes (all-cause mortality, cardiovascular mortality, sudden cardiac death [SCD], aborted SCD, heart failure hospitalization) after carefully reviewed. A meta-analysis was performed to calculate pooled odds ratios (OR) with 95% confidence intervals (CIs) for prognostic outcomes in LGE positive versus LGE negative patients with DCM. Five studies for 545 DCM patients were contained in this meta-analysis. The results showed LGE positive patients was significantly associated with higher cardiovascular mortality (pooled OR: 2.67; 95% CI: 1.12-6.35; p=0.03), aborted SCD (pooled OR: 5.26; 95% CI: 1.57-17.55; p=0.007), and heart failure hospitalization (pooled OR: 3.91; 95% CI: 1.99-7.69; p<0.001). Late gadolinium enhancement during cardiac MRI is significantly associated with cardiovascular mortality, aborted SCD and heart failure hospitalization in DCM patients. The LGE can be a potential stratification tool to predict the risk of cardiac events among patients with DCM.
    Saudi medical journal 07/2013; 34(7):719-26. · 0.62 Impact Factor
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    ABSTRACT: IRF4, a member of the interferon regulatory factor (IRF) family, was previously shown to be restricted in the immune system and involved in the differentiation of immune cells. However, we interestingly observed that IRF4 was also highly expressed in both human and animal hearts. Given that several transcription factors have been shown to regulate the pathological cardiac hypertrophy, we then ask whether IRF4, as a new transcription factor, plays a critical role in pressure overload-elicited cardiac remodeling. A transgenic mouse model with cardiac-specific overexpression of IRF4 was generated and subjected to an aortic banding for 4 to 8 weeks. Our results demonstrated that overexpression of IRF4 aggravated pressure overload-triggered cardiac hypertrophy, fibrosis, and dysfunction. Conversely, IRF4 knockout mice showed an attenuated hypertrophic response to chronic pressure overload. Mechanistically, we discovered that the expression and activation of cAMP response element-binding protein (CREB) were significantly increased in IRF4-overexpressing hearts, while being greatly reduced in IRF4-KO hearts on aortic banding, compared with control hearts, respectively. Similar results were observed in ex vivo cultured neonatal rat cardiomyocytes on the treatment with angiotensin II. Inactivation of CREB by dominant-negative mutation (dnCREB) offset the IRF4-mediated hypertrophic response in angiotensin II-treated myocytes. Furthermore, we identified that the promoter region of CREB contains 3 IRF4 binding sites. Altogether, these data indicate that IRF4 functions as a necessary modulator of hypertrophic response by activating the transcription of CREB in hearts. Thus, our study suggests that IRF4 might be a novel target for the treatment of pathological cardiac hypertrophy and failure.
    Hypertension 04/2013; · 6.87 Impact Factor
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    ABSTRACT: Interferon regulatory factor (IRF) 3, a member of the highly conserved IRF family transcription factors, plays a pivotal role in innate immune response, apoptosis, and oncogenesis. Recent studies have implicated IRF3 in a wide range of host defense. However, whether IRF3 induces defensive responses to hypertrophic stresses such as biomechanical stress and neurohumoral factors remains unclear. Herein, we employed an IRF3-deficient mouse model, cardiac-specific IRF3-overexpression mouse model and isolated cardiomyocytes to investigate the role of IRF3 in cardiac hypertrophy induced by aortic banding (AB) or isoproterenol (ISO). The extent of cardiac hypertrophy was quantitated by echocardiography as well as by pathological and molecular analysis. Our results demonstrate that IRF3 deficiency profoundly exacerbated cardiac hypertrophy, whereas overexpression of IRF3 in the heart significantly blunted pathological cardiac remodeling induced by pressure overload. Similar results were also observed in cultured cardiomyocytes upon the treatment with ISO. Mechanistically, we discovered that IRF3 interacted with ERK2 and thereby inhibited the ERK1/2 signaling. Furthermore, inactivation of ERK1/2 by U0126 offset the IRF3-deficient-mediated hypertrophic response induced by aortic banding. Altogether, these data demonstrate that IRF3 plays a protective role in AB-induced hypertrophic response by inactivating ERK1/2 in the heart. Therefore, IRF3 could be a new target for the prevention and therapy of cardiac hypertrophy and failure.
    Archiv für Kreislaufforschung 03/2013; 108(2):326. · 7.35 Impact Factor
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    ABSTRACT: Cardiac remodeling is a key determinant in the clinical course and outcome of heart failure and characterized by cardiac hypertrophy, fibrosis, cardiomyocyte apoptosis and inflammation. The anti-inflammatory, anti-apoptotic and anti-fibrotic effects of paeoniflorin have been identified in various types of tissue and cells. However, the role of paeoniflorin in cardiac remodeling remains unclear. We performed aortic banding (AB) in mice to induce a cardiac remodeling model in response to pressure overload. Paeoniflorin (20 mg/kg) was administered by daily intraperitoneal (i.p.) injection. Paeoniflorin treatment promoted the survival rate and improved cardiac function of mice at 8 weeks post surgery. AB-induced cardiac hypertrophy, as assessed by heart weight, gross heart, HE and WGA staining, cross-sectional area of cardiomyocyte and mRNA expresssion of hypertrophic makers, was attenuated by paeoniflorin. Paeoniflorin also inhibited collagen deposition, expression of TGFβ, CTGF, collagen Iα and collagen IIIα, and phosphorylation of Smad2 and Smad3 in the heart exposed to pressure overload. Cardiomyocyte apoptosis and induction of Bax and cleaved caspase3 in response to AB were suppressed by paeoniflorin. Furthermore, paeoniflorin decreased the quantity of CD68+ cells, protein levels of TNF-α and IL-1β, and phosphorylation of IκBα and NFκB-p65 in the heart after AB. In conclusion, paeoniflorin attenuated cardiac hypertrophy, fibrosis, apoptosis and inflammation, and improved left ventricular function in pressure overloaded mice. The cardioprotective effect of paeoniflorin is associated with the inhibition of TGFβ/Smads and NF-κB pathways.
    Journal of molecular histology 02/2013; · 1.75 Impact Factor
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    ABSTRACT: 3,3'-Diindolylmethane (DIM) is a natural component of cruciferous plants. It has strong antioxidant and anti-angiogenic effects and promotes the apoptosis of a variety of tumor cells. However, little is known about the critical role of DIM on cardiac hypertrophy. In the present study, we investigated the effects of DIM on cardiac hypertrophy. Multiple molecular techniques such as Western blot analysis, real-time PCR to determine RNA expression levels of hypertrophic, fibrotic and oxidative stress markers, and histological analysis including H&E for histopathology, PSR for collagen deposition, WGA for myocyte cross-sectional area, and immunohistochemical staining for protein expression were used. In pre-treatment and reverse experiments, C57/BL6 mouse chow containing 0.05% DIM (dose 100 mg/kg/d DIM) was administered one week prior to surgery or one week after surgery, respectively, and continued for 8 weeks after surgery. In both experiments, DIM reduced to cardiac hypertrophy and fibrosis induced by aortic banding through the activation of 5'-adenosine monophosphate-activated protein kinase-α2 (AMPKα2) and inhibition of mammalian target of the rapamycin (mTOR) signaling pathway. Furthermore, DIM protected against cardiac oxidative stress by regulating expression of estrogen-related receptor-alpha (ERRα) and NRF2 etc. The cardioprotective effects of DIM were ablated in mice lacking functional AMPKα2. DIM significantly improves left ventricular function via the activation of AMPKα2 in a murine model of cardiac hypertrophy.
    PLoS ONE 01/2013; 8(1):e53427. · 3.73 Impact Factor
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    ABSTRACT: The inducible IκB kinase (IKKi/IKKε) is a recently described serine-threonine IKK-related kinase. Previous studies have reported the role of IKKi in infectious diseases and cancer. However, its role in the cardiac response to pressure overload remains elusive. In this study, we investigated the effects of IKKi deficiency on the development of pathological cardiac hypertrophy using in vitro and in vivo models. First, we developed mouse models of pressure overload cardiac hypertrophy induced by pressure overload using aortic banding (AB). Four weeks after AB, cardiac function was then assessed through echocardiographic and hemodynamic measurements. Western blotting, real-time PCR and histological analyses were used to assess the pathological and molecular mechanisms. We observed that IKKi-deficient mice showed significantly enhanced cardiac hypertrophy, cardiac dysfunction, apoptosis and fibrosis compared with WT mice. Furthermore, we recently revealed that the IKKi-deficient mice spontaneously develop cardiac hypertrophy. Moreover, in vivo experiments showed that IKKi deficiency-induced cardiac hypertrophy was associated with the activation of the AKT and NF-κB signaling pathway in response to AB. In cultured cells, IKKi overexpression suppressed the activation of this pathway. In conclusion, we demonstrate that IKKi deficiency exacerbates cardiac hypertrophy by regulating the AKT and NF-κB signaling pathway.
    PLoS ONE 01/2013; 8(1):e53412. · 3.73 Impact Factor
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    ABSTRACT: Baicalein, a flavonoid present in the root of Scutellaria baicalensis, is well known for its antibacterial, antiviral, anti-inflammatory antithrombotic and antioxidant effects. Here we show that baicalein also attenuates cardiac hypertrophy. Aortic banding(AB) was performed to induce cardiac hypertrophy secondary to pressure overload in mice. Mouse chow containing 0.05% baicalein (dose: 100mg/kg/d baicalein) was begun one week prior to surgery and continued for 8 weeks after surgery. Our data demonstrated that baicalein prevented cardiac hypertrophy and fibrosis induced by AB, as assessed by echocardiographic and hemodynamic parameters and by pathological and molecular analysis. The inhibitory action of baicalein on cardiac hypertrophy was mediated by effects on mitogen activated protein kinase kinase (MEK)-extracellular signal-regulated kinases (ERK1/2) signaling and GATA-4 activation. In vitro studies performed in rat cardiac H9c2 cells confirmed that baicalein attenuated cardiomyocyte hypertrophy induced by angiotensin II, which was associated with inhibiting MEK-ERK1/2 signaling. In conclusion, our results suggest that baicalein has protective potential for targeting cardiac hypertrophy and fibrosis through suppression of MEK-ERK1/2 signaling. Baicalein warrants further research as a potential antihypertrophic agent that might be clinically useful to treat cardiac hypertrophy and heart failure. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 12/2012; · 3.06 Impact Factor
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    ABSTRACT: Stem cell antigen (Sca) 1, a glycosyl phosphatidylinositol-anchored protein localized to lipid rafts, is upregulated in the heart during myocardial infarction and renovascular hypertension-induced cardiac hypertrophy. It has been suggested that Sca-1 plays an important role in myocardial infarction. To investigate the role of Sca-1 in cardiac hypertrophy, we performed aortic banding in Sca-1 cardiac-specific transgenic mice, Sca-1 knockout mice, and their wild-type littermates. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. Sca-1 expression was upregulated and detected in cardiomyocytes after aortic banding surgery in wild-type mice. Sca-1 transgenic mice exhibited significantly attenuated cardiac hypertrophy and fibrosis and preserved cardiac function compared with wild-type mice after 4 weeks of aortic banding. Conversely, Sca-1 knockout dramatically worsened cardiac hypertrophy, fibrosis, and dysfunction after pressure overload. Furthermore, aortic banding-induced activation of Src, mitogen-activated protein kinases, and Akt was blunted by Sca-1 overexpression and enhanced by Sca-1 deficiency. Our results suggest that Sca-1 protects against cardiac hypertrophy and fibrosis via regulation of multiple pathways in cardiomyocytes.
    Hypertension 07/2012; 60(3):802-9. · 6.87 Impact Factor
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    ABSTRACT: Cardiac hypertrophy is a response of the myocardium to increased workload and is characterised by an increase of myocardial mass and an accumulation of extracellular matrix (ECM). As an ECM protein, an integrin ligand, and an angiogenesis inhibitor, all of which are key players in cardiac hypertrophy, mindin is an attractive target for therapeutic intervention to treat or prevent cardiac hypertrophy and heart failure. In this study, we investigated the role of mindin in cardiac hypertrophy using littermate Mindin knockout (Mindin ( -/- )) and wild-type (WT) mice. Cardiac hypertrophy was induced by aortic banding (AB) or angiotensin II (Ang II) infusion in Mindin ( -/- ) and WT mice. The extent of cardiac hypertrophy was quantitated by echocardiography and by pathological and molecular analyses of heart samples. Mindin ( -/- ) mice were more susceptible to cardiac hypertrophy and fibrosis in response to AB or Ang II stimulation than wild type. Cardiac function was also markedly exacerbated during both systole and diastole in Mindin ( -/- ) mice in response to hypertrophic stimuli. Western blot assays further showed that the activation of AKT/glycogen synthase kinase 3β (GSK3β) signalling in response to hypertrophic stimuli was significantly increased in Mindin ( -/- ) mice. Moreover, blocking AKT/GSK3β signalling with a pharmacological AKT inhibitor reversed cardiac abnormalities in Mindin ( -/- ) mice. Our data show that mindin, as an intrinsic cardioprotective factor, prevents maladaptive remodelling and the transition to heart failure by blocking AKT/GSK3β signalling.
    Journal of Molecular Medicine 02/2012; 90(8):895-910. · 4.77 Impact Factor
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    ABSTRACT: Mindin is a secreted extracellular matrix protein, an integrin ligand, and an angiogenesis inhibitor, other examples of which are all key players in the progression of cardiac hypertrophy. However, its function during cardiac hypertrophy remains unclear. This study was aimed to identify the effect of mindin on cardiac hypertrophy and the underlying mechanisms. A significant down-regulation of mindin expression was observed in human failing hearts. To further investigate the role of mindin in cardiac hypertrophy, we used cultured neonatal rat cardiomyocytes with gain and loss of mindin function and cardiac-specific Mindin-overexpressing transgenic (TG) mice. In cultured cardiomyocytes, mindin negatively regulated angiotensin II (Ang II)-mediated hypertrophic growth, as detected by [(3)H]-Leucine incorporation, cardiac myocyte area, and hypertrophic marker protein levels. Cardiac hypertrophy in vivo was produced by aortic banding (AB) or Ang II infusion in TG mice and their wild-type controls. The extent of cardiac hypertrophy was evaluated by echocardiography as well as by pathological and molecular analyses of heart samples. Mindin overexpression in the heart markedly attenuated cardiac hypertrophy, fibrosis, and left ventricular dysfunction in mice in response to AB or Ang II. Further analysis of the signalling events in vitro and in vivo indicated that these beneficial effects of mindin were associated with the interruption of AKT/glycogen synthase kinase 3β (GSK3β) and transforming growth factor (TGF)-β1-Smad signalling. The present study demonstrates for the first time that mindin serves as a novel mediator that protects against cardiac hypertrophy and the transition to heart failure by blocking AKT/GSK3β and TGF-β1-Smad signalling.
    Cardiovascular research 06/2011; 92(1):85-94. · 5.80 Impact Factor
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    ABSTRACT: Cardiac hypertrophy, a major determinant of heart failure, is associated with heat shock proteins (HSPs). HSP75 has been reported to protect against environmental stresses; however, its roles in cardiac hypertrophy remain unclear. Here, we generated cardiac-specific inducible HSP75 transgenic mice (TG) and cardiac hypertrophy was developed at 4 weeks after aortic banding in TG mice and wild-type littermates. The results revealed that overexpression of HSP75 prevented cardiac hypertrophy and fibrosis as assessed by heart weight/body weight ratio, heart weight/tibia length ratio, echocardiographic and hemodynamic parameters, cardiomyocyte width, left ventricular collagen volume, and gene expression of hypertrophic markers. Further studies showed that overexpression of HSP75 inhibited the activation of TAK/P38, JNK, and AKT signaling pathways. Thus, HSP75 likely reduces the hypertrophy and fibrosis induced by pressure overload through blocking TAK/P38, JNK, and AKT signaling pathways.
    Journal of Cellular Biochemistry 03/2011; 112(7):1787-94. · 3.06 Impact Factor
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    ABSTRACT: Activating transcription factor 3 (ATF3), which is encoded by an adaptive-response gene induced by various stimuli, plays an important role in the cardiovascular system. However, the effect of ATF3 on cardiac hypertrophy induced by a pathological stimulus has not been determined. Here, we investigated the effects of ATF3 deficiency on cardiac hypertrophy using in vitro and in vivo models. Aortic banding (AB) was performed to induce cardiac hypertrophy in mice. Cardiac hypertrophy was estimated by echocardiographic and hemodynamic measurements and by pathological and molecular analysis. ATF3 deficiency promoted cardiac hypertrophy, dysfunction and fibrosis after 4 weeks of AB compared to the wild type (WT) mice. Furthermore, enhanced activation of the MEK-ERK1/2 and JNK pathways was found in ATF3-knockout (KO) mice compared to WT mice. In vitro studies performed in cultured neonatal mouse cardiomyocytes confirmed that ATF3 deficiency promotes cardiomyocyte hypertrophy induced by angiotensin II, which was associated with the amplification of MEK-ERK1/2 and JNK signaling. Our results suggested that ATF3 plays a crucial role in the development of cardiac hypertrophy via negative regulation of the MEK-ERK1/2 and JNK pathways.
    PLoS ONE 01/2011; 6(10):e26744. · 3.73 Impact Factor
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    Free Radical Biology and Medicine. 11/2010; 49(8):1323.
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    ABSTRACT: The development of cardiac hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response that may eventually lead to ventricular dilatation and heart failure. Cellular FLICE-inhibitory protein (cFLIP) is a homologue of caspase 8 without caspase activity that inhibits apoptosis initiated by death receptor signaling. Previous studies showed that cFLIP expression was markedly decreased in the ventricular myocardium of patients with end-stage heart failure. However, the critical role of cFLIP on cardiac remodeling remains unclear. To specifically determine the role of cFLIP in pathological cardiac remodeling, we used heterozygote cFLIP(+/-) mice and transgenic mice with cardiac-specific overexpression of the human cFLIP(L) gene. Our results demonstrated that the cFLIP(+/-) mice were susceptible to cardiac hypertrophy and fibrosis through inhibition of mitogen-activated protein kinase kinase-extracellular signal-regulated kinase 1/2 signaling, whereas the transgenic mice displayed the opposite phenotype in response to angiotensin II stimulation. These studies indicate that cFLIP protein is a crucial component of the signaling pathway involved in cardiac remodeling and heart failure.
    Hypertension 10/2010; 56(6):1109-17. · 6.87 Impact Factor

Publication Stats

217 Citations
131.89 Total Impact Points

Institutions

  • 2009–2014
    • Wuhan University
      • Department of Cardiology
      Wu-han-shih, Hubei, China
  • 2009–2013
    • Renmin University of China
      Peping, Beijing, China
  • 2010
    • Sun Yat-Sen University
      • Department of Cardiology
      Guangzhou, Guangdong Sheng, China
    • Massachusetts General Hospital
      • Cardiovascular Research Center
      Boston, MA, United States