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Wei Deng,
Jing Zong,
Zhouyan Bian,
Heng Zhou,
Yuan Yuan,
Rui Zhang,
Haipeng Guo,
Yan Zhang,
Difei Shen, Hongliang Li,
Qizhu Tang
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ABSTRACT: SCOPE: Indole-3-carbinol (I3C), a monomer component extracted from leaves and stems of cruciferous vegetables, has inhibitory effects on tumors, obesity, and liver fibrosis, but its effects on the development of cardiac remodeling remain completely unknown. We determined the effects of I3C on cardiac remodeling and heart function using an aortic banding (AB) mouse model. METHODS AND RESULTS: Male 8- to10-wk-old wild-type and 5' adenosine monophosphate-activated protein kinase (AMPK)-α2 knockout mice fed with or without I3C were subjected to AB or a sham operation and were phenotyped, accordingly. I3C both prevented and reversed cardiac remodeling induced by AB, as assessed by heart weight/body weight, lung weight/body weight, and heart weight/tibia length ratios, echocardiographic and hemodynamic parameters, histological analysis, and gene expression of hypertrophic and fibrotic markers. The inhibitory effect of I3C on cardiac remodeling was mediated by AMPK-α and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling. Moreover, AMPK-α2 gene deficiency completely blocked the inhibitory effects of I3C on cardiac remodeling, preventing the improvements in heart weight/body weight, lung weight/body weight, heart weight/tibia length, cardiac function, gene expression of hypertrophic and fibrotic markers, and phosphorylation of mammalian target of rapamycin and ERK1/2 signaling components. CONCLUSION: I3C both prevents and reverses cardiac remodeling by activating AMPK-α signaling. I3C is a potential therapeutic drug for heart failure.
Molecular Nutrition & Food Research 04/2013; · 4.30 Impact Factor
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Ding-Sheng Jiang,
Zhou-Yan Bian,
Yan Zhang,
Shu-Min Zhang,
Yi Liu,
Rui Zhang,
Yingjie Chen,
Qinglin Yang,
Xiao-Dong Zhang,
Guo-Chang Fan, Hongliang Li
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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; · 6.21 Impact Factor
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Xin-An Wang,
Ran Zhang,
Dingsheng Jiang,
Wei Deng,
Shumin Zhang,
Shan Deng,
Jinfeng Zhong,
Tao Wang,
Li-Hua Zhu,
Li Yang,
Shufen Hong,
Sen Guo,
Ke Chen,
Xiao-Fei Zhang,
Zhigang She,
Yingjie Chen,
Qinglin Yang,
Xiao-Dong Zhang, Hongliang Li
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ABSTRACT: Obesity is a calorie excessive state that is associated with high risk of diabetes, atherosclerosis and certain types of tumors. Obesity may induce inflammation and insulin resistance. We found that the expression of interferon regulatory factor 9 (IRF9), a major transcription factor mediating interferon (IFN) responses, was lower in the livers of obese mice than in those of their lean counterparts. Furthermore, whole-body IRF9 knockout (KO) mice were more obese and had aggravated insulin resistance, hepatic steatosis and inflammation after chronic high-fat diet (HFD) feeding. In contrast, adenoviral-mediated hepatic IRF9 overexpression in both diet-induced and genetically (ob/ob) obese mice showed markedly improved hepatic insulin sensitivity and attenuated hepatic steatosis and inflammation. We further employed a yeast two-hybrid screening system to investigate the interactions between IRF9 and its cofactors. Importantly, we identified that IRF9 interacts with peroxisome proliferator-activated receptor α (PPARα), an important metabolism-associated nuclear receptor, to activate PPARα target genes. In addition, liver-specific PPARα overexpression rescued insulin sensitivity and ameliorated hepatic steatosis and inflammation in IRF9 KO mice. Taken together, our results indicate that IRF9 attenuates hepatic insulin resistance, steatosis and inflammation through interaction with PPARα. (HEPATOLOGY 2013.).
Hepatology 03/2013; · 11.66 Impact Factor
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Ke Chen,
Lu Gao,
Yu Liu,
Yan Zhang,
Ding-Sheng Jiang,
Xiang Wei,
Xue Hai Zhu,
Rui Zhang,
Yingjie Chen,
Qinglin Yang,
Noriyuki Kioka,
Xiao-Dong Zhang, Hongliang Li
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ABSTRACT: Cardiac hypertrophy is the heart's response to hypertrophic stimuli and is associated with increased mortality. Vinexin-β is a vinculin-binding protein that belongs to a family of adaptor proteins and mediates signal transduction and actin cytoskeleton organisation. A previous study has shown that Vinexin-β is ubiquitously expressed and that it is highly expressed in the heart. However, a critical role for Vinexin-β in cardiac hypertrophy has not been investigated. Therefore, to examine the role of Vinexin-β in pathological cardiac hypertrophy, we used Vinexin-β knockout mice and transgenic mice that overexpress human Vinexin-β in the heart. Cardiac hypertrophy was induced by aortic banding (AB). The extent of cardiac hypertrophy was quantitated by echocardiography and pathological and molecular analyses of heart samples. Our results demonstrated that Vinexin-β overexpression in the heart markedly attenuated cardiac hypertrophy, fibrosis, and cardiac dysfunction, whereas loss of Vinexin-β exaggerated the pathological cardiac remodelling and fibrosis response to pressure overload. Further analysis of the in vitro and in vivo signalling events indicated that beneficial Vinexin-β effects were associated with AKT signalling abrogation. Our findings demonstrate for the first time that Vinexin-β is a novel mediator that protects against cardiac hypertrophy by blocking the AKT signalling pathway.
Archiv für Kreislaufforschung 03/2013; 108(2):338. · 7.35 Impact Factor
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Jing Lu,
Zhou-Yan Bian,
Ran Zhang,
Yan Zhang,
Chen Liu,
Ling Yan,
Shu-Min Zhang,
Ding-Sheng Jiang,
Xiang Wei,
Xue Hai Zhu,
Manyin Chen,
Ai-Bing Wang,
Yingjie Chen,
Qinglin Yang,
Peter P Liu, Hongliang Li
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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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Lang Wang,
Yanyun Lu,
Hongjing Guan,
Dingsheng Jiang,
Yu Guan,
Xin Zhang,
Hiroyasu Nakano,
Yan Zhou,
Yan Zhang,
Li Yang, Hongliang Li
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ABSTRACT: BACKGROUND: Tumor necrosis factor receptor-associated factor 5 (TRAF5) is an adaptor protein of the tumor necrosis factor (TNF) receptor superfamily and the interleukin-1 receptor/Toll-like receptor superfamily and plays important roles in regulating multiple signaling pathways. The role of TRAF5 in the context of brain ischemia/reperfusion (I/R) injury has not yet been examined. METHODS AND RESULTS: Transient occlusion of the middle cerebral artery was performed on TRAF5 knockout mice (KO), neuron-specific TRAF5 transgene (TG) and the appropriate controls. Compared with the WT mice, the TRAF5 KO mice showed lower infarct volumes and better outcomes in the neurological tests. A low neuronal apoptosis level, an attenuated blood brain barrier (BBB) disruption and an inhibited inflammatory response were exhibited in TRAF5 KO mice. TRAF5 TG mice exhibited an opposite phenotype. Moreover, the Akt/FoxO1 signaling pathway was enhanced in the ischemic brains of the TRAF5 KO mice. CONCLUSIONS: TRAF5 KO mice exhibited minor infarctions, low levels of neuronal apoptosis, an attenuated BBB disruption and an inhibited inflammatory response following cerebral I/R injury. These data demonstrate that TRAF5 is a critical mediator of I/R injury in an experimental stroke model. The Akt /FoxO1 signaling pathway probably plays an important role in the biological function of TRAF5 in this model. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12207.
Journal of Neurochemistry 02/2013; · 4.06 Impact Factor
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Lang Wang,
Yanyun Lu,
Xin Zhang,
Yan Zhang,
Dingsheng Jiang,
Xiaomin Dong,
Shan Deng,
Li Yang,
Yu Guan,
Lihua Zhu,
Yan Zhou,
Xiaodong Zhang, Hongliang Li
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ABSTRACT: BACKGROUND: Stroke is the second leading cause of death among adults worldwide. Mindin is an ECM protein that plays important roles in regulating inflammation, angiogenesis and neuronal outgrowth. The role of mindin in the context of brain ischemia has not been examined. METHODS AND RESULTS: Transient occlusion of the middle cerebral artery was performed on mindin knockout (KO) mice, mice that carried a neuron-specific constitutively active mindin transgene (TG) and the appropriate controls. The outcome of the ischemia was evaluated by examination of the infarct and edema volumes and by neurological score assessments. The brains were collected 24 hours or 3 days following the induced stroke. Compared with the control mice, the mindin KO mice exhibited lower infarct volumes and better outcomes in the neurological tests. Mindin-deficient mice exhibited low expression levels of stroke-induced inflammatory mediators, an attenuated recruitment of inflammatory cells, and inhibited activation of NF-κB. The neuronal apoptosis levels were also lower in the brains of the mindin KO mice than in those of the control mice. The mice that expressed a neuron-specific, constitutively active mindin transgene exhibited effects following the cerebral ischemic injury that were the opposite of those that were observed in the mindin KO mice. Moreover, Akt signaling activation was elevated in the ischemic brains of mindin KO mice. CONCLUSIONS: Mindin KO mice exhibited minor infarctions, an attenuated inflammatory response and low levels of neuronal apoptosis following an ischemic insult. These data demonstrate that mindin is a critical mediator of ischemic brain injury in an experimental stroke model. Akt signaling most likely mediates the biological function of mindin in this model of cerebral ischemia.
Experimental Neurology 01/2013; · 4.70 Impact Factor
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Xin-An Wang,
Shan Deng,
Dingsheng Jiang,
Ran Zhang,
Shumin Zhang,
Jinfeng Zhong,
Li Yang,
Tao Wang,
Shufen Hong,
Sen Guo,
Zhigang She,
Xiao-Dong Zhang, Hongliang Li
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ABSTRACT: Caspase activation and recruitment domain 3 (CARD3) is a 61-kDa protein kinase with an N-terminal serine/threonine kinase domain and a C-terminal CARD. Previous research on the function of CARD3 has focused on its role in the immune response and inflammatory diseases. Obesity is now a worldwide health problem and is generally recognized as an inflammatory disease. Unexpectedly, we found that CARD3 expression was lower during obesity. In this study, we explored the biological and genetic bases of obesity using CARD3-knockout (KO) and wild-type (WT) mice fed a high-fat diet (HFD) for 24 weeks. We demonstrate that KO mice were more obese than their WT littermates, and KO mice exhibited obvious visceral fat accumulation and liver weight gains after 24 weeks of HFD feeding. We also observed more severe hepatosteatosis in KO mice compared with the WT controls. Hepatic steatosis in the HFD-fed KO mice was linked to a significant increase in the expression of key lipogenic and cholesterol synthesis enzymes, whereas the expression of the enzymes involves in β-oxidation was dramatically reduced. Furthermore, we confirmed the repression of AMP-activated protein kinase signaling and activation of the endoplasmic reticulum stress response. Fatty liver impaired the global glucose and lipid metabolism, which further exacerbated the insulin resistance associated with the repression of Akt signaling and up-regulated systemic inflammation through the M1/M2 (pro- and anti-inflammation) type switch and the activation of the nuclear factor-κB pathway. Our studies demonstrate the crucial role of CARD3 in metabolism and indicate that CARD3 deficiency promotes the diet-induced phenotype of type 2 diabetes.
Endocrinology 01/2013; · 4.46 Impact Factor
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ABSTRACT: The aim of this study was to elucidate the effects of regulator of G-protein signaling 5 (Rgs5), a negative regulator of G-protein-mediated signaling, on cardiac repolarization and arrhythmia in mice. Wild-type and Rgs5(-/-) mice were subjected to in vivo, in vitro, and cellular electrophysiological experiments. Rgs5(-/-) mouse hearts showed significantly prolonged cardiac repolarization, including prolonged QT interval and action potential duration (APD). Consistent with these findings, measurement of K(+) currents in ventricular myocytes of Rgs5(-/-) mice revealed significant reduction of the outward voltage-dependent K(+) currents, including I(peak), I(to,)I(Kur), and I(ss), compared to that in wild-type mice. Transcript and protein expression levels of Kv4.2, Kv4.3, Kv1.5, and Kv2.1 were downregulated in Rgs5(-/-) mouse ventricles compared with those in wild-type mice (P<0.05). In addition, electrically induced ventricular tachyarrhythmias were facilitated by Rgs5(-/-) in isolated hearts. Importantly, the increased incidence and duration of electrically induced ventricular tachyarrhythmias were associated with enhanced dispersion of APD and spatial heterogeneity of I(peak), I(to) and I(Kur) between the epicardium and endocardium in the Rgs5(-/-) heart. This study showed the relationship between the absence of Rgs5 and cardiac electrophysiological abnormality. The results strongly indicate that Rgs5(-/-) induced prolonged repolarization and ventricular tachyarrhythmia, which were closely related to the remodeling of voltage-dependent K(+) currents.
Journal of Molecular and Cellular Cardiology 10/2012; · 5.17 Impact Factor
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Heng Zhou,
Zhou-Yan Bian,
Jing Zong,
Wei Deng,
Ling Yan,
Di-Fei Shen,
Haipeng Guo,
Jia Dai,
Yuan Yuan,
Rui Zhang,
Ya-Fen Lin,
Xue Hu, Hongliang Li,
Qi-Zhu Tang
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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. · 6.21 Impact Factor
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ABSTRACT: Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that has been shown to repress inflammatory gene expression in multiple cell types and diseases. This study was conducted to investigate the role of ATF3 in the pathological processes of cerebral ischemia and its influence on post-ischemic inflammation.
Wild-type (WT) and ATF3 knockout (KO) mice were subjected to middle cerebral artery occlusion (45 min) followed by reperfusion. Infarct volume, brain edema, and neurological deficits were examined. Neural apoptosis, inflammatory gene expression, cellular inflammatory response and Matrix Metallo Proteinases 9 (MMP9) activity were assessed. Activity of the nuclear factor-kappa B (NF-κB) signaling pathway and cAMP-responsive element-binding protein (CREB) was studied.
Knockout of ATF3 significantly exacerbated the infarct volume and worsened neurological function after brain ischemia. Neural apoptosis, inflammatory gene expression and cellular inflammatory response were upregulated in ATF3 KO mice. The MMP9 mRNA expression and protein activity were increased in ATF3 KO mice. KO of ATF3 led to an elevation in the activity of the NF-κB signaling pathway and inhibition of CREB activity.
Our study demonstrated that ATF3 was markedly induced by brain ischemia. ATF3 deficiency exacerbated the inflammatory response and brain injury after cerebral ischemia, potentially through further activation of the NF-κB signaling pathway. ATF3 is likely an important protective regulator in cerebral ischemic injury.
Neuroscience 06/2012; 220:100-8. · 3.38 Impact Factor
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ABSTRACT: Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), also known as Signal-regulatory protein alpha (SIRPα) or SIRPA is a transmembrane protein that is predominantly expressed in neurons, dendritic cells, and macrophages. This study was conducted to investigate the role of SHPS-1 in the oxidative stress and brain damage induced by acute focal cerebral ischemia. Wild-type (WT) and SHPS-1 mutant (MT) mice were subjected to middle cerebral artery occlusion (60 min) followed by reperfusion. SHPS-1 MT mice had significantly reduced infarct volumes and improved neurological function after brain ischemia. In addition, neural injury and oxidative stress were inhibited in SHPS-1 MT mice. The mRNA and protein levels of the antioxidant genes nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase 1 were up-regulated in SHPS-1 MT mice. The SHPS-1 mutation suppressed the phosphorylation of SHP-1 and SHP-2 and increased the phosphorylation of Akt and GSK3β. These results provide the first demonstration that SHPS-1 plays an important role in the oxidative stress and brain injury induced by acute cerebral ischemia. The activation of Akt signaling and the up-regulation of Nrf2 and heme oxygenase 1 likely account for the protective effects that were observed in the SHPS-1 MT mice.
Journal of Neurochemistry 06/2012; 122(4):834-43. · 4.06 Impact Factor
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Zhou-Yan Bian,
Xiang Wei,
Shan Deng,
Qi-Zhu Tang,
Jinghua Feng,
Yan Zhang,
Chen Liu,
Ding-Sheng Jiang,
Ling Yan,
Lian-Feng Zhang,
Manyin Chen,
John Fassett,
Yingjie Chen,
You-Wen He,
Qinglin Yang,
Peter P Liu, Hongliang Li
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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. · 4.67 Impact Factor
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ABSTRACT: AIMS: The aim of this study was to elucidate the effects of regulator of G-protein signaling 5 (Rgs5), a negative regulator of G protein-mediated signaling, on atrial repolarization and tachyarrhythmia (ATA) in mice. METHODS AND RESULTS: In present study, the incidence of ATA were increased in Rgs5(-/-) Langendorff-perfused mouse hearts during program electrical stimulation (PES) (46.7%, 7 of 15) and burst pacing (26.7%, 4 of 15) compared with wild-type (WT) mice (PES: 7.1%,1 of 14; burst:7.1%,1 of 14) (P<0.05). And the duration of ATA also shown longer in Rgs5(-/-) heart than that in WT, 2 out of 15 hearts exhibited sustained ATA (>30 s) but none of them observed in WT mice. Atrial prolonged repolarization was observed in Rgs5(-/-) hearts including widened P wave in surface ECG recording, increased action potential duration (APD) and atrial effective refractory periods (AERP), all of them showed significant difference with WT mice (P<0.05). At the cellular level, whole-cell patch clamp recorded markedly decreased densities of repolarizing K(+) currents including I(Kur) (at +60 mV: 14.0±2.2 pF/pA) and I(to) (at +60 mV: 16.7±1.3 pA/pF) in Rgs5(-/-) atrial cardiomyocytes, compared to those of WT mice (at +60 mV I(to): 20.4±2.0 pA/pF; I(kur): 17.9±2.0 pF/pA) (P<0.05). CONCLUSION: These results suggest that Rgs5 is an important regulator of arrhythmogenesis in the mouse atrium and that the enhanced susceptibility to atrial tachyarrhythmias in Rgs5(-/-) mice may contribute to abnormalities of atrial repolarization.
PLoS ONE 01/2012; 7(11):e46856. · 4.09 Impact Factor
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ABSTRACT: The effect of regulator of G protein signaling 5 (RGS5) on cardiac hypertrophy, atherosclerosis and angiogenesis has been well demonstrated, but the role in the development of obesity and insulin resistance remains completely unknown. We determined the effect of RGS5 deficiency on obesity, hepatic steatosis, inflammation and insulin resistance in mice fed either a normal-chow diet (NC) or a high-fat diet (HF).
Male, 8-week-old RGS5 knockout (KO) and littermate control mice were fed an NC or an HF for 24 weeks and were phenotyped accordingly. RGS5 KO mice exhibited increased obesity, fat mass and ectopic lipid deposition in the liver compared with littermate control mice, regardless of diet. When fed an HF, RGS5 KO mice had a markedly exacerbated metabolic dysfunction and inflammatory state in the blood serum. Meanwhile, macrophage recruitment and inflammation were increased and these increases were associated with the significant activation of JNK, IκBα and NF-κBp65 in the adipose tissue, liver and skeletal muscle of RGS5 KO mice fed an HF relative to control mice. These exacerbated metabolic dysfunction and inflammation are accompanied with decreased systemic insulin sensitivity in the adipose tissue, liver and skeletal muscle of RGS5 KO mice, reflected by weakened Akt/GSK3β phosphorylation.
Our data suggest that loss of RGS5 exacerbates HF-induced obesity, hepatic steatosis, inflammation and insulin resistance.
PLoS ONE 01/2012; 7(1):e30256. · 4.09 Impact Factor
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Jinfeng Xiao,
Mark Moon,
Ling Yan,
Min Nian,
Yan Zhang,
Chen Liu,
Jing Lu,
Hongjing Guan,
Manyin Chen,
Dingsheng Jiang,
Hong Jiang,
Peter P Liu, Hongliang Li
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ABSTRACT: Cellular FLICE-inhibitory protein (cFLIP) is a member of the tumour necrosis factor signalling pathway and a regulator of apoptosis, and it has a role in cardiac remodelling following myocardial infarction (MI) that remains largely uncharacterised. This study aimed to determine the function of cFLIP as a potential mediator of post-infarction cardiac remodelling. Our results show diminished cFLIP expression in failing human and murine post-infarction hearts. Genetically engineered cFLIP heterozygous (cFLIP+/-, HET) mice, cardiac-specific cFLIP-overexpressing transgenic (TG) mice and their respective wild-type (WT) and non-transgenic controls were subjected to MI by permanent ligation of their left anterior descending artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Apoptosis, inflammation, angiogenesis, and fibrosis were evaluated in the myocardium. The HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and remodelling compared with WT mice 28 days after MI. Impaired LV function in the HET mice was associated with increases in infarct size, hypertrophy, apoptosis, inflammation, and interstitial fibrosis, and reduced capillary density. The TG mice displayed the opposite phenotype after MI. Moreover, adenovirus-mediated overexpression of cFLIP decreased LV dilatation and improved LV function and remodelling in both HET and WT mice. Further analysis of signalling events suggests that cFLIP promotes cardioprotection by interrupting JNK1/2 signalling and augmenting Akt signalling. In conclusion, our results indicate that cFLIP protects against the development of post-infarction cardiac remodelling. Thus, cFLIP gene delivery shows promise as a clinically powerful and novel therapeutic strategy for the treatment of heart failure after MI.
Archiv für Kreislaufforschung 01/2012; 107(1):239. · 7.35 Impact Factor
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ABSTRACT: Epidermal growth factor (EGF), latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) is developmentally upregulated in the heart. Little is known about the relationship between ELTD1 and cardiac diseases. Therefore, we aimed to clarify the role of ELTD1 in pressure overload-induced cardiac hypertrophy.
C57BL/6J wild-type (WT) mice and ELTD1-knockout (KO) mice were subjected to left ventricular pressure overload by descending aortic banding (AB). KO mice exhibited more unfavorable cardiac remodeling than WT mice 28 days post AB; this remodeling was characterized by aggravated cardiomyocyte hypertrophy, thickening of the ventricular walls, dilated chambers, increased fibrosis, and blunted systolic and diastolic cardiac function. Analysis of signaling pathways revealed enhanced extracellular signal-regulated kinase (ERK) and the c-Jun amino-terminal kinase (JNK) phosphorylation in response to ELTD1 deletion.
ELTD1 deficiency exacerbates cardiac hypertrophy and cardiac function induced by AB-induced pressure overload by promoting both cardiomyocyte hypertrophy and cardiac fibrosis. These effects are suggested to originate from the activation of the ERK and JNK pathways, suggesting that ELTD1 is a potential target for therapies that prevent the development of cardiac disease.
PLoS ONE 01/2012; 7(5):e35779. · 4.09 Impact Factor
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Ling Yan,
Xiang Wei,
Qi-Zhu Tang,
Jinghua Feng,
Yan Zhang,
Chen Liu,
Zhou-Yan Bian,
Lian-Feng Zhang,
Manyin Chen,
Xue Bai,
Ai-Bing Wang,
John Fassett,
Yingjie Chen,
You-Wen He,
Qinglin Yang,
Peter P Liu, Hongliang Li
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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: 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. · 4.09 Impact Factor
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Hongliang Li,
Qi-Zhu Tang,
Chen Liu,
Mark Moon,
Manyin Chen,
Ling Yan,
Zhou-Yan Bian,
Yan Zhang,
Ai-Bing Wang,
Mai P Nghiem,
Peter P Liu
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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. · 6.21 Impact Factor
