Li-Hua Zhu

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

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Publications (28)164.83 Total impact

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    ABSTRACT: Hepatic ischemia/reperfusion (I/R) injury often occurs during liver surgery and may cause liver failure. Our previous studies revealed that Mindin is involved in the pathogenesis of ischemic stroke. However, the function of Mindin in hepatic I/R injury remains unknown. Partial hepatic warm ischemia was induced in parallel in global Mindin knockout mice (Mindin KO), hepatocyte-specific Mindin knockdown mice, hepatocyte-specific Mindin transgenic mice (Mindin TG), myeloid cell-specific Mindin TG mice (LysM-Mindin-TG), and their corresponding controls, followed by reperfusion. Hepatic histology, serum aminotransferase, inflammatory cytokines, and hepatocyte apoptosis and proliferation were examined to assess liver injury. The molecular mechanisms of Mindin function were explored in vivo and in vitro. Mindin KO and hepatocyte-specific Mindin knockdown mice exhibited less liver damage than controls, with smaller necrotic areas and lower serum transaminase levels. Mindin deficiency significantly suppressed inflammatory cell infiltration, cytokine and chemokine production, and hepatocyte apoptosis, but increased hepatocyte proliferation following hepatic I/R injury. In contrast, the opposite pathological and biochemical changes were observed in hepatocyte-specific Mindin TG mice, whereas no significant changes in liver damage were found in LysM-Mindin-TG mice compared to NTG controls. Mechanistically, AKT signaling was activated in livers of Mindin KO mice but was suppressed in Mindin TG mice. Most importantly, AKT inhibitor treatment blocked the protective effect of Mindin deficiency on hepatic I/R injury. Mindin is a novel modulator of hepatic I/R injury through regulating inflammatory responses, as well as hepatocyte apoptosis and proliferation via inactivation of the AKT signaling pathway. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · Journal of Hepatology
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    ABSTRACT: Mindin/spondin 2, an extracellular matrix (ECM) component that belongs to the thrombospondin type 1 (TSR) class of molecules, plays prominent roles in the regulation of inflammatory responses, angiogenesis and metabolic disorders. Our most recent studies indicated that mindin is largely involved in the initiation and development of cardiac and cerebrovascular diseases. However, the regulatory functions of mindin in neointima formation remain unclear. In the present study, mindin expressions were significantly downregulated in platelet-derived growth factor-BB (PDGF-BB)-stimulated vascular smooth muscle cells (VSMCs) and wire injury-stimulated vascular tissue. Using a gain-of-function approach, overexpression of mindin in VSMCs exhibited strong anti-proliferative and anti-migratory effects on VSMCs, while significant suppression of intimal hyperplasia was observed in transgenic (TG) mice expressing mindin specifically in SMCs. These mice exhibited blunted VSMC proliferation, migration, and phenotypic switching. Conversely, deletion of mindin dramatically exacerbated neointima formation in a wire-injury mouse model, which was further confirmed in a balloon injury-induced vascular lesion model using a novel mindin-KO rat strain. From mechanistic standpoint, the AKT-GSK3β/mTOR-FOXO3A-FOXO1 signaling axis is responsible for the regulation of mindin during intimal thickening. Interestingly, an AKT inhibitor largely reversed mindin-KO-induced aggravated hyperplasia, suggesting that mindin-mediated neointima formation is AKT-dependent. Taken together, our findings demonstrate that mindin protects against vascular hyperplasia by suppression of abnormal VSMC proliferation, migration, and phenotypic switching in an AKT-dependent manner. Upregulation of mindin might represent an effective therapy for vascular remodeling-related diseases.
    No preview · Article · Mar 2015 · Clinical Science
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    ABSTRACT: Interferon regulatory factor 9 (IRF9) has various biological functions and regulates cell survival; however, its role in vascular biology has not been explored. Here we demonstrate a critical role for IRF9 in mediating neointima formation following vascular injury. Notably, in mice, IRF9 ablation inhibits the proliferation and migration of vascular smooth muscle cells (VSMCs) and attenuates intimal thickening in response to injury, whereas IRF9 gain-of-function promotes VSMC proliferation and migration, which aggravates arterial narrowing. Mechanistically, we show that the transcription of the neointima formation modulator SIRT1 is directly inhibited by IRF9. Importantly, genetic manipulation of SIRT1 in smooth muscle cells or pharmacological modulation of SIRT1 activity largely reverses the neointima-forming effect of IRF9. Together, our findings suggest that IRF9 is a vascular injury-response molecule that promotes VSMC proliferation and implicate a hitherto unrecognized 'IRF9-SIRT1 axis' in vasculoproliferative pathology modulation.
    Full-text · Article · Oct 2014 · Nature Communications
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    ABSTRACT: Background Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factor family, plays important roles in innate immunity and immune cell differentiation. However, the role of IRF7 in neointima formation is currently unknown. Methods and Results Significant decreases in IRF7 expression were observed in vascular smooth muscle cells (VSMCs) following carotid artery injury in vivo and platelet‐derived growth factor‐BB (PDGF‐BB) stimulation in vitro. Compared with non‐transgenic (NTG) controls, SMC‐specific IRF7 transgenic (IRF7‐TG) mice displayed reduced neointima formation and VSMC proliferation in response to carotid injury, whereas a global knockout of IRF7 (IRF7‐KO) resulted in the opposite effect. Notably, a novel IRF7‐KO rat strain was successfully generated and used to further confirm the effects of IRF7 deletion on the acceleration of intimal hyperplasia based on a balloon injury‐induced vascular lesion model. Mechanistically, IRF7's inhibition of carotid thickening and the expression of VSMC proliferation markers was dependent on the interaction of IRF7 with activating transcription factor 3 (ATF3) and its downstream target, proliferating cell nuclear antigen (PCNA). The evidence that IRF7/ATF3‐double‐TG (DTG) and IRF7/ATF3‐double‐KO (DKO) mice abolished the regulatory effects exhibited by the IRF7‐TG and IRF7‐KO mice, respectively, validated the underlying molecular events of IRF7‐ATF3 interaction. Conclusions These findings demonstrated that IRF7 modulated VSMC proliferation and neointima formation by interacting with ATF3, thereby inhibiting the ATF3‐mediated induction of PCNA transcription. The results of this study indicate that IRF7 is a novel modulator of neointima formation and VSMC proliferation and may represent a promising target for vascular disease therapy.
    Preview · Article · Sep 2014 · Journal of the American Heart Association
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    ABSTRACT: The failure of past efforts to develop effective stroke treatments is at least partially because these treatments often interfered with essential physiological functions, even though they are targeted toward pathophysiological events, such as inflammation, excitotoxicity, and oxidative stress. Thus, the direct targeting of endogenous neuroprotective or destructive elements holds promise as a potential new approach to treating this devastating condition. Interferon regulatory factor 9 (IRF9), a transcription factor that regulates innate immune responses, has been implicated in neurological pathology. Here, we provide new evidence that IRF9 directly mediates neuronal death in male mice. In response to ischemia/reperfusion (I/R), IRF9 accumulated in neurons. IRF9 deficiency markedly mitigated both poststroke neuronal death and neurological deficits, whereas the neuron-specific overexpression of IRF9 sensitized neurons to death. The histone deacetylase Sirt1 was identified as a novel negative transcriptional target of IRF9 both in vivo and in vitro. IRF9 inhibits Sirt1 deacetylase activity, culminating in the acetylation and activation of p53-mediated cell death signaling. Importantly, both the genetic and pharmacological manipulation of Sirt1 effectively counteracted the pathophysiological effects of IRF9 on stroke outcome. These findings indicate that, rather than activating a delayed innate immune response, IRF9 directly activates neuronal death signaling pathways through the downregulation of Sirt1 deacetylase in response to acute I/R stress.
    Full-text · Article · Sep 2014 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Background & aims: Hepatic ischemia/reperfusion (I/R) injury is characterized by anoxic cell injury and the generation of inflammatory mediators, leading to hepatic parenchymal cell death. The activation of interferon regulatory factors (IRFs) has been implicated in hepatic I/R injury, but the role of IRF9 in this progression is unclear. Methods: We investigated the function and molecular mechanisms of IRF9 in transgene and knockout mice subjected to warm I/R of the liver. Isolated hepatocytes from IRF9 transgene and knockout mice were subjected to hypoxia/reoxygenation (H/R) injury to determine the in vitro effects of IRF9. Results: The injuries were augmented in IRF9-overexpressing mice that were subjected to warm I/R of the liver. In contrast, a deficiency in IRF9 markedly reduced the necrotic area, serum alanine amino transferase/aspartate amino transferase (ALT/AST), immune cell infiltration, inflammatory cytokine levels, and hepatocyte apoptosis after liver I/R. Sirtuin (SIRT) 1 levels were significantly higher and the acetylation of p53 was decreased in the IRF9 knockout mice. Notably, IRF9 suppressed the activity of the SIRT1 promoter luciferase reporter and deacetylase activity. Liver injuries were significantly more severe in the IRF9/SIRT1 double knockout (DKO) mice in the I/R model, eliminating the protective effects observed in the IRF9 knockout mice. Conclusions: IRF9 has a novel function of inducing hepatocyte apoptosis after I/R injury by decreasing SIRT1 expression and increasing acetyl-p53 levels. Targeting IRF9 may be a potential strategy for ameliorating ischemic liver injury after liver surgery.
    No preview · Article · Aug 2014 · Journal of Hepatology
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    ABSTRACT: Vascular smooth muscle cell (VSMC) proliferation is central to the pathophysiology of neointima formation. Interferon regulatory factor 3 (IRF3) inhibits the growth of cancer cells, and fibroblasts. However, the role of IRF3 in vascular neointima formation is unknown. We evaluated the protective role of IRF3 against neointima formation in mice and the underlying mechanisms.Methods and ResultsIRF3 expression was downregulated in VSMCs after carotid wire injury in vivo, and in SMCs after PDGF-BB challenge in vitro. Global knockout of IRF3 (IRF3-KO) led to accelerated neointima formation and proliferation of VSMCs, whereas the opposite was seen in SMC-specific IRF3 transgenic mice. Mechanistically, we identified IRF3 as a novel regulator of peroxisome proliferator-activated receptors γ (PPARγ), a negative regulator of SMC proliferation after vascular injury. Binding of IRF3 to the AB domain of PPARγ in the nucleus of SMCs facilitated PPARγ transactivation, resulting in decreased proliferation cell nuclear antigen (PCNA) expression and suppressed proliferation. Overexpression of wild-type but not truncated IRF3 with a mutated IAD domain retained the ability to exert anti-proliferative effect. IRF3 inhibits VSMC proliferation and neointima formation after vascular injury through PPARγ activation.
    No preview · Article · Mar 2014 · Cardiovascular Research
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    ABSTRACT: Unlabelled: Obesity and related metabolic diseases associated with chronic low-grade inflammation greatly compromise human health. Previous observations on the roles of interferon regulatory factors (IRFs) in the regulation of metabolism prompted investigation of the involvement of a key family member, IRF3, in metabolic disorders. IRF3 expression in the liver is decreased in animals with diet-induced and genetic obesity. The global knockout (KO) of IRF3 significantly promotes chronic high-fat diet (HFD)-induced hepatic insulin resistance and steatosis; in contrast, adenoviral-mediated hepatic IRF3 overexpression preserves glucose and lipid homeostasis. Furthermore, systemic and hepatic inflammation, which is increased in IRF3 KO mice, is attenuated by the overexpression of hepatic IRF3. Importantly, inhibitor of nuclear factor kappa B kinase beta subunit / nuclear factor kappa B (IKKβ/NF-κB) signaling is repressed by IRF3, and hepatic overexpression of the inhibitor of κB-α (IκBα) reverses HFD-induced insulin resistance and steatosis in IRF3 KO mice. Mechanistically, IRF3 interacts with the kinase domain of IKKβ in the cytoplasm and inhibits its downstream signaling. Moreover, deletion of the region of IRF3 responsible for the IRF3/IKKβ interaction inhibits the capacity of IRF3 to preserve glucose and lipid homeostasis. Conclusion: IRF3 interacts with IKKβ in the cytoplasm to inhibit IKKβ/NF-κB signaling, thus alleviating hepatic inflammation, insulin resistance, and hepatic steatosis.
    No preview · Article · Mar 2014 · Hepatology
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    ABSTRACT: Obesity and its related pathologies, such as hepatic steatosis, are associated with chronic inflammation and insulin resistance (IR), which contribute to cardiovascular disease. Our previous studies indicated that Spondin 2 has a protective role in the context of cardiovascular and cerebrovascular diseases. Whether Spondin 2 is also associated with the development of hepatic steatosis and IR remains unclear. Wild-type mice, Spondin 2-knockout (KO) mice, hepatic-specific Spondin 2 transgenic (Spondin 2-TG) mice, high fat diet (HFD)-induced obese mice injected with an adenovirus expressing Spondin 2-specific shRNA or a Spondin 2 mutant and genetically obese (ob/ob) mice injected with an adenovirus expressing Spondin 2 were fed normal chow (NC) or HFD for indicated time to induce obesity, hepatic steatosis, inflammation and IR. Biomedical, histological and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms of Spondin 2's functions were explored in mice and in hepatocytes or cell lines. Consistent with Spondin 2 repression in the livers of HFD-induced and ob/ob mice, the Spondin 2-KO or hepatic-specific Spondin 2 knockdown mice exhibited more severe obesity, hepatic steatosis, inflammation and IR upon HFD. Conversely, these pathological conditions were significantly improved in the Spondin 2-TG mice or Spondin 2-overexpressing ob/ob mice. Spondin 2 interacts with PPARα to regulate PPARα-target genes, thereby improving the pathological phenotypes. In contrast, the hepatic overexpression of mutant Spondin 2 without the PPARα-interacting domain failed to improve the aggravated phenotypes observed in the Spondin 2-KO mice. Spondin 2 regulates hepatic lipid metabolism and alleviates hepatic steatosis, obesity, inflammation and IR in mice via its interaction with PPARα.
    No preview · Article · Jan 2014 · Journal of Hepatology
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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.
    Full-text · Article · Jan 2014 · Cardiovascular Research
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    ABSTRACT: Interferon regulatory factor 8 (IRF8), a member of the IRF transcription factor family, was recently implicated in vascular diseases. In the present study, using the mouse left carotid artery wire injury model, we unexpectedly observed that the expression of IRF8 was greatly enhanced in smooth muscle cells (SMCs) by injury. Compared with the wild-type controls, IRF8 global knockout mice exhibited reduced neointimal lesions and maintained SMC marker gene expression. We further generated SMC-specific IRF8 transgenic mice using an SM22α-driven IRF8 plasmid construct. In contrast to the knockout mice, mice with SMC-overexpressing IRF8 exhibited a synthetic phenotype and enhanced neointima formation. Mechanistically, IRF8 inhibited SMC marker gene expression through regulating serum response factor (SRF) transactivation in a myocardin-dependent manner. Furthermore, a coimmunoprecipitation assay indicated a direct interaction of IRF8 with myocardin, in which a specific region of myocardin was essential for recruiting acetyltransferase p300. Altogether, IRF8 is crucial in modulating SMC phenotype switching and neointima formation in response to vascular injury via direct interaction with the SRF/myocardin complex.
    Preview · Article · Nov 2013 · Molecular and Cellular Biology
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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.
    Full-text · Article · Oct 2013 · Hypertension
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    ABSTRACT: Unlabelled: Obesity is a calorie-excessive state associated with high risk of diabetes, atherosclerosis, and certain types of tumors. Obesity may induce inflammation and insulin resistance (IR). We found that the expression of interferon (IFN) regulatory factor 9 (IRF9), a major transcription factor mediating IFN responses, was lower in livers of obese mice than in those of their lean counterparts. Furthermore, whole-body IRF9 knockout (KO) mice were more obese and had aggravated IR, hepatic steatosis, and inflammation after chronic high-fat diet 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 alpha (PPAR-α), an important metabolism-associated nuclear receptor, to activate PPAR-α target genes. In addition, liver-specific PPAR-α overexpression rescued insulin sensitivity and ameliorated hepatic steatosis and inflammation in IRF9 KO mice. Conclusion: IRF9 attenuates hepatic IR, steatosis, and inflammation through interaction with PPAR-α.
    Preview · Article · Aug 2013 · Hepatology
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    ABSTRACT: The aim of the present study was to determine the effect of baicalein on metabolic syndrome induced by a high-fat diet in mice. The mice developed obesity, dyslipidemia, fatty liver, diabetes and insulin resistance. These disorders were effectively normalized in baicalein-treated mice. Further investigation revealed that the inhibitory effect on inflammation and insulin resistance was mediated by inhibition of the MAPKs pathway and activation of the IRS1/PI3K/Akt pathway. The lipid-lowering effect was attributed to the blocking of synthesis way mediated by SERBP-1c, PPARγ and the increased fatty acid oxidation. All of these effects depended on AMPKα activation. These results were confirmed in the primary hepatocytes from wild type and AMPKα2−/− mice. However, the IRS-1/PI3K/AKT pathway showed no change, which may be due to the time of stimulation and concentration. Thus, these data suggested that baicalein protects mice from metabolic syndrome through an AMPKα2-dependent mechanism involving multiple intracellular signaling pathways.
    No preview · Article · Oct 2012 · Molecular and Cellular Endocrinology
  • Hong Jiang · Si-si Chen · Jian Yang · Jing Chen · Bo He · Li-hua Zhu · Lang Wang
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    ABSTRACT: Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases. Recent evidence from our group suggested that CREB-binding protein (CBP) plays an important role in thrombin-induced EPCs migration. However, whether CBP could regulate EPCs angiogenic properties is unknown. In the present study, we investigated whether CBP silencing could inhibit thrombin-induced EPCs angiogenesis. EPCs isolated from the bone marrow of Sprague-Dawley rats were cultured and identified, and then were treated by thrombin alone or combined with CBP-shRNA lentivirus. The effect of CBP silencing on EPCs proliferation was assessed using BrdU incorporation assay. Cell adhesion and tube formation were detected to evaluate the angiogenic functions. Finally, mRNA and protein expression of relevant angiogenic genes were examined by real-time PCR, western-blot, and enzyme-linked immunoassay respectively. Luciferase reporter gene assay was performed to evaluate NF-κB activity. Administration of thrombin significantly promoted EPCs proliferation and adhesion. Thrombin also increased the tube formation in Matrigel assay. However, these effects of thrombin were abolished by CBP gene silencing. CBP silencing also abrogated thrombin-induced increases of integrin β2 expression. In thrombin-induced EPCs, CBP silencing significantly decreased the secretion of VEGF, IL-6 and suppressed NF-κB activity. In conclusion, thrombin-induced EPCs proliferation, adhesion, and tube formation were inhibited by CBP silencing, indicating that CBP plays an important role in thrombin-induced EPCs neovascularization.
    No preview · Article · Jun 2011 · Molecular Biology Reports
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    ABSTRACT: Vascular smooth muscle cell (VSMC) proliferation and migration are crucial events involved in the pathophysiology of vascular diseases. Sirtuin 1 (SIRT1), a class III histone deacetylase (HDAC), has been reported to have the function of antiatherosclerosis, but its role in neointima formation remains unknown. The present study was designed to investigate the role of SIRT1 in the regulation of neointima formation and to elucidate the underlying mechanisms. A decrease in SIRT1 expression was observed following carotid artery ligation. smooth muscle cell (SMC)-specific human SIRT1 transgenic (Tg) mice were generated. SIRT1 overexpression substantially inhibited neointima formation after carotid artery ligation or carotid artery wire injury. In the intima of injured carotid arteries, VSMC proliferation (proliferating cell nuclear antigen (PCNA)-positive cells) was significantly reduced. SIRT1 overexpression markedly inhibited VSMC proliferation and migration and induced cell cycle arrest at G1/S transition in vitro. Accordingly, SIRT1 overexpression decreased the induction of cyclin D1 and matrix metalloproteinase-9 (MMP-9) expression by treatment with serum and TNF-α, respectively, whereas RNAi knockdown of SIRT1 resulted in the opposite effect. Decreased cyclin D1 and MMP-9 expression/activity were also observed in injured carotid arteries from SMC-SIRT1 Tg mice. Furthermore, 2 targets of SIRT1, c-Fos and c-Jun, were involved in the downregulation of cyclin D1 and MMP-9 expression. Our findings demonstrate the inhibitory effect of SIRT1 on the VSMC proliferation and migration that underlie neointima formation and implicate SIRT1 as a potential target for intervention in vascular diseases.
    Preview · Article · May 2011 · Circulation Research
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    Hong Jiang · Jing Chen · Lang Wang · Li-hua Zhu · Hua-zhi Wen
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    ABSTRACT: Thrombin acts as a potent mitogenic factor for ECs (endothelial cells) by the release of several growth factors, including PDGF-B (platelet-derived growth factor-B). CBP (CREB-binding protein), which functions as a transcriptional coactivator, links the changes in the extracellular stimuli with alterations in gene expression. Therefore, we hypothesized that CBP could mediate thrombin-induced proliferation of ECs via PDGF-B-dependent way. Short hairpin RNA was used to down-regulate the expression of CBP in ECs. CBP and PDGF-B levels were analysed by real-time RT-PCR and Western blot. To evaluate ECs proliferation, cell cycle and DNA synthesis were analysed by flow cytometry and BrdU (bromodeoxyuridine) incorporation assay, respectively. PDGF-B was involved in the mitogenic effect of thrombin on ECs. Down-regulation of CBP attenuated ECs proliferation and inhibited cell cycle progression induced by thrombin. Silencing CBP expression also suppressed thrombin-induced PDGF-B expression in ECs. Mitogenic activity of thrombin was impaired by silencing CBP expression in ECs. This inhibitory effect was, in part, related to the inability to up-regulate PDGF-B expression in ECs. CBP could be regarded as a potential therapeutic target for vascular injury.
    Preview · Article · Dec 2010 · Cell Biology International
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    Full-text · Article · Nov 2010 · Free Radical Biology and Medicine
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    ABSTRACT: The excess generation of reactive oxygen species (ROS) play important role in the development and progression of diabetes and related vascular complications. Therefore, blocking the production of ROS will be able to improve hyperglycemia-induced vascular dysfunction. The objective of this study was to determine whether a novel IH636 grape seed proanthocyanidins (GSPs) could protect against hyperproliferation of cultured rat vascular smooth muscle cells (VSMCs) induced by high glucose (HG) and determine the related molecular mechanisms. Our data demonstrated that GSPs markedly inhibited rat VSMCs proliferation as well as ROS generation and NAPDH oxidase activity induced by HG treatment. Further studies revealed that HG treatment resulted in phosphorylation and membrane translocation of Rac1, p47phox, and p67phox subunits leading to NADPH oxidase activation. GSPs treatment remarkably disrupted the phosphorylation and membrane translocation of Rac1, p47phox, and p67phox subunits. More importantly, our data further revealed that GSPs significantly disrupted HG-induced activation of ERK1/2, JNK1/2, and PI3K/AKT/GSK3beta as well as NF-kappaB signalings, which were dependent on reactive oxygen species (ROS) generation and Rac1 activation. In addition, our results also demonstrated that HG-induced cell proliferation and excess ROS production was dependent on the activation of PI3 kinase subunit p110alpha. Collectively, these results suggest that HG-induced VSMC growth was attenuated by grape seed proanthocyanidin (GSPs) treatment through blocking PI3 kinase-dependent signaling pathway, indicating that GSPs may be useful in retarding intimal hyperplasia and restenosis in diabetic vessels.
    No preview · Article · Jun 2010 · Journal of Cellular Physiology
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    ABSTRACT: Breviscapine is a mixture of flavonoid glycosides extracted from the Chinese herbs. Previous studies have shown that breviscapine possesses comprehensive pharmacological functions. However, very little is known about whether breviscapine have protective role on cardiac hypertrophy. The aim of the present study was to determine whether breviscapine attenuates cardiac hypertrophy induced by angiotensin II (Ang II) in cultured neonatal rat cardiac myocytes in vitro and pressure-overload-induced cardiac hypertrophy in mice in vivo. Our data demonstrated that breviscapine (2.5-15 microM) dose-dependently blocked cardiac hypertrophy induced by Ang II (1 microM) in vitro. The results further revealed that breviscapine (50 mg/kg/day) prevented cardiac hypertrophy induced by aortic banding as assessed by heart weight/body weight and lung weight/body weight ratios, echocardiographic parameters, and gene expression of hypertrophic markers. The inhibitory effect of breviscapine on cardiac hypertrophy is mediated by disrupting PKC-alpha-dependent ERK1/2 and PI3K/AKT signaling. Further studies showed that breviscapine inhibited inflammation by blocking NF-kappaB signaling, and attenuated fibrosis and collagen synthesis through abrogating Smad2/3 signaling. Therefore, these findings indicate that breviscapine, which is a potentially safe and inexpensive therapy for clinical use, has protective potential in targeting cardiac hypertrophy and fibrosis through suppression of PKC-alpha-dependent signaling.
    No preview · Article · Apr 2010 · Journal of Cellular Biochemistry