Publications by authors named "Guang-Nian Zhao"

20 Publications

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SIMPLE is an endosomal regulator that protects against non-alcoholic fatty liver disease by targeting the lysosomal degradation of EGFR.

Hepatology 2021 Jul 28. Epub 2021 Jul 28.

Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) has become a tremendous burden for public health, however, there is no drug for NAFLD therapy at present. Impaired endo-lysosome-mediated protein degradation is observed in a variety of metabolic disorders, such as atherosclerosis, type 2 diabetes mellitus and NAFLD. Small integral membrane protein of lysosome/late endosome (SIMPLE) is a regulator of endosome-to-lysosome trafficking and cell signaling. But the role that SIMPLE plays in NAFLD progression remains unknown. Here we investigated SIMPLE function in NAFLD development and sophisticated mechanism therein.

Approach & Results: This study found in vitro knockdown of SIMPLE significantly aggravated lipid accumulation, inflammation in hepatocytes treated with metabolic stimulation. Consistently, in vivo experiments showed that liver-specific Simple-knockout (Simple-HKO) mice exhibited more severe high-fat diet (HFD)-, high-fat-high-cholesterol diet (HFHC)-, and methionine-choline-deficient diet (MCD)- induced steatosis, glucose intolerance, inflammation, and fibrosis than those fed with normal-chow diet. Meanwhile, RNA-sequencing demonstrated the up-regulated signaling pathways and signature genes involved in lipid metabolism, inflammation and fibrosis in Simple-HKO mice compared to control mice under metabolic stress. Mechanically, we found SIMPLE directly interact with epidermal growth factor receptor (EGFR). SIMPLE deficiency results in dysregulated degradation of EGFR, subsequently hyperactivated EGFR phosphorylation, exaggerating NAFLD development. Moreover, we further demonstrated that using EGFR inhibitor or silencing EGFR expression could ameliorate lipid accumulation induced by the knockdown of SIMPLE.

Conclusions: SIMPLE ameliorated NASH by prompting EGFR degradation and can also be a potential therapeutic candidate for NASH.
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http://dx.doi.org/10.1002/hep.32075DOI Listing
July 2021

TMBIM1 is an inhibitor of adipogenesis and its depletion promotes adipocyte hyperplasia and improves obesity-related metabolic disease.

Cell Metab 2021 Aug 8;33(8):1640-1654.e8. Epub 2021 Jun 8.

Medical Science Research Center, Zhongnan Hospital, School of Basic Medical Sciences, Wuhan University, Wuhan, China; Institute of Model Animal, Wuhan University, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Huanggang Institute of Translational Medicine, Huanggang, China. Electronic address:

Obesity is characterized by the excessive accumulation of the white adipose tissue (WAT), but healthy expansion of WAT via adipocyte hyperplasia can offset the negative metabolic effects of obesity. Thus, identification of novel adipogenesis regulators that promote hyperplasia may lead to effective therapies for obesity-induced metabolic disorders. Using transcriptomic approaches, we identified transmembrane BAX inhibitor motif-containing 1 (TMBIM1) as an inhibitor of adipogenesis. Gain or loss of function of TMBIM1 in preadipocytes inhibited or promoted adipogenesis, respectively. In vivo, in response to caloric excess, adipocyte precursor (AP)-specific Tmbim1 knockout (KO) mice displayed WAT hyperplasia and improved systemic metabolic health, while overexpression of Tmbim1 in transgenic mice showed the opposite effects. Moreover, mature adipocyte-specific Tmbim1 KO did not affect WAT cellularity or nutrient homeostasis. Mechanistically, TMBIM1 binds to and promotes the autoubiquitination and degradation of NEDD4, which is an E3 ligase that stabilizes PPARγ. Our data show that TMBIM1 is a potent repressor of adipogenesis and a potential therapeutic target for obesity-related metabolic disease.
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http://dx.doi.org/10.1016/j.cmet.2021.05.014DOI Listing
August 2021

The Neutrophil-to-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19.

Cell Metab 2021 02 5;33(2):258-269.e3. Epub 2021 Jan 5.

Department of Neonatology, Renmin Hospital of Wuhan University, Wuhan, China.

Corticosteroid therapy is now recommended as a treatment in patients with severe COVID-19. But one key question is how to objectively identify severely ill patients who may benefit from such therapy. Here, we assigned 12,862 COVID-19 cases from 21 hospitals in Hubei Province equally to a training and a validation cohort. We found that a neutrophil-to-lymphocyte ratio (NLR) > 6.11 at admission discriminated a higher risk for mortality. Importantly, however, corticosteroid treatment in such individuals was associated with a lower risk of 60-day all-cause mortality. Conversely, in individuals with an NLR ≤ 6.11 or with type 2 diabetes, corticosteroid treatment was not associated with reduced mortality, but rather increased risks of hyperglycemia and infections. These results show that in the studied cohort corticosteroid treatment is associated with beneficial outcomes in a subset of COVID-19 patients who are non-diabetic and with severe symptoms as defined by NLR.
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http://dx.doi.org/10.1016/j.cmet.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832609PMC
February 2021

In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.

Cell Metab 2020 08 24;32(2):176-187.e4. Epub 2020 Jun 24.

Department of Intensive Care Unit, Wuhan Third Hospital & Tongren Hospital of Wuhan University, Wuhan, China.

Statins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.
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http://dx.doi.org/10.1016/j.cmet.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311917PMC
August 2020

Targeting Transmembrane BAX Inhibitor Motif Containing 1 Alleviates Pathological Cardiac Hypertrophy.

Circulation 2018 04 11;137(14):1486-1504. Epub 2017 Dec 11.

Department of Cardiology, Renmin Hospital of Wuhan University, China (K.-Q.D., Z.W., P.Z., Z.-G.S., H.L.)

Background: Cardiac hypertrophy and its resultant heart failure are among the most common causes of mortality worldwide. Abnormal protein degradation, especially the impaired lysosomal degradation of large organelles and membrane proteins, is involved in the progression of cardiac hypertrophy. However, the underlying mechanisms have not been fully elucidated.

Methods: We investigated cardiac transmembrane BAX inhibitor motif containing 1 (TMBIM1) mRNA and protein expression levels in samples from patients with heart failure and mice with aortic banding (AB)-induced cardiac hypertrophy. We generated cardiac-specific knockout mice and cardiac-specific -overexpressing transgenic mice and then challenged them with AB surgery. We used microarray, confocal image, and coimmunoprecipitation analyses to identify the downstream targets of TMBIM1 in cardiac hypertrophy. / double-knockout mice were generated to investigate whether the effects of TMBIM1 on cardiac hypertrophy were Toll-like receptor 4 (TLR4) dependent. Finally, lentivirus-mediated overexpression in a monkey AB model was performed to evaluate the therapeutic potential of TMBIM1.

Results: TMBIM1 expression was significantly downregulated on hypertrophic stimuli in both human and mice heart samples. Silencing cardiac aggravated AB-induced cardiac hypertrophy. This effect was blunted by overexpression. Transcriptome profiling revealed that the TLR4 signaling pathway was disrupted dramatically by manipulation of . The effects of TMBIM1 on cardiac hypertrophy were shown to be dependent on TLR4 in double-knockout mice. Fluorescent staining indicated that TMBIM1 promoted the lysosome-mediated degradation of activated TLR4. Coimmunoprecipitation assays confirmed that TMBIM1 directly interacted with tumor susceptibility gene 101 via a PTAP motif and accelerated the formation of multivesicular bodies that delivered TLR4 to the lysosomes. Finally, lentivirus-mediated overexpression reversed AB-induced cardiac hypertrophy in monkeys.

Conclusions: TMBIM1 protects against pathological cardiac hypertrophy through promoting the lysosomal degradation of activated TLR4. Our findings reveal the central role of TMBIM1 as a multivesicular body regulator in the progression of pathological cardiac hypertrophy, as well as the role of vesicle trafficking in signaling regulation during cardiac hypertrophy. Moreover, targeting TMBIM1 could be a novel therapeutic strategy for treating cardiac hypertrophy and heart failure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.031659DOI Listing
April 2018

Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4.

Nat Med 2017 Jun 8;23(6):742-752. Epub 2017 May 8.

Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.

Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. There is currently no pharmacological therapy for NASH. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases; however, whether it can serve as a therapeutic target for NAFLD and NASH remains unknown. Here we report that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. Tmbim1 expression in hepatocytes substantially inhibited high-fat diet-induced insulin resistance, hepatic steatosis and inflammation in mice. Mechanistically, Tmbim1 promoted the lysosomal degradation of toll-like receptor 4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process. We also found that overexpression of Tmbim1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. Taken together, these findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.
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http://dx.doi.org/10.1038/nm.4334DOI Listing
June 2017

Cardiac-Specific EPI64C Blunts Pressure Overload-Induced Cardiac Hypertrophy.

Hypertension 2016 May 28;67(5):866-77. Epub 2016 Mar 28.

From the Division of Cardiothoracic and Vascular Surgery (X.Z, J.F., X.W.), Heart-Lung Transplantation Center (X.Z., J.F., X.W.), Sino-Swiss Heart-Lung Transplantation Institute (X.Z., J.F., X.W.), Department of Medical Ultrasound (H.-Y.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.); and Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China (J.G., J.-H.G.,G.-N.Z., Y.-X.J., H.L.).

The calcium-responsive molecule, calcineurin, has been well characterized to play a causal role in pathological cardiac hypertrophy over the past decade. However, the intrinsic negative regulation of calcineurin signaling during the progression of cardiomyocyte hypertrophy remains enigmatic. Herein, we explored the role of EPI64C, a dual inhibitor of both Ras and calcineurin signaling during T-cell activation, in pressure overload-induced cardiac hypertrophy. We generated a cardiac-specific Epi64c conditional knockout mouse strain and showed that loss of Epi64c remarkably exacerbates pressure overload-induced cardiac hypertrophy. In contrast, EPI64C gain-of-function in cardiomyocyte-specific Epi64c transgenic mice exerts potent protective effects against cardiac hypertrophy. Mechanistically, the cardioprotective effects of EPI64C are largely attributed to the disrupted calcineurin signaling but are independent of its Ras suppressive capability. Molecular studies have indicated that the 406 to 446 C-terminal amino acids in EPI64C directly bind to the 287 to 337 amino acids in the catalytic domain of calcineurin, which is responsible for the EPI64C-mediated suppressive effects. We further extrapolated our studies to cynomolgus monkeys and showed that gene therapy based on lentivirus-mediated EPI64C overexpression in the monkey hearts blunted pressure overload-induced cardiac hypertrophy. Our study thus identified EPI64C as a novel negative regulator in cardiac hypertrophy by targeting calcineurin signaling and demonstrated the potential of gene therapy and drug development for treating cardiac hypertrophy.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.07042DOI Listing
May 2016

DKK3 expression in hepatocytes defines susceptibility to liver steatosis and obesity.

J Hepatol 2016 07 23;65(1):113-124. Epub 2016 Mar 23.

Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430071, China; Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China. Electronic address:

Background & Aims: Dickkopf-3 (DKK3), a protein belonging to the DKK family, has been extensively investigated in the context of cancer, including liver cancer. However, the role of DKK3 in hepatic steatosis and related metabolic disorders remains largely unexplored.

Methods: We detected the expression of DKK3 in the fatty livers of NAFLD patients and of obese mice and investigated the function of DKK3 in hepatic steatosis and related metabolic disorders by using hepatocyte-specific DKK3 deficiency or overexpression obese mice induced by high fat diet (HFD) or genetic defect (ob/ob). The molecular mechanisms underlying DKK3-regulated hepatic steatosis were further explored and verified in mice.

Results: DKK3 expression was significantly decreased in the livers of NAFLD patients and of obese mice as well as in cultured hepatocytes stimulated with palmitate. Further investigation indicated that specific overexpression of DKK3 in hepatocytes enhanced insulin sensitivity and glucose tolerance, reduced the inflammatory response, and ameliorated the imbalance of lipid metabolism in response to HFD or genetic defects. In contrast, DKK3 deficiency in hepatocytes led to an almost complete reversal of these pathologies. Mechanistically, DKK3 combined with Apoptosis signal-regulating kinase 1 (ASK1) under palmitate stimulation, and thus inhibited the activation of the downstream P38/JNK pathway. Importantly, dominant-negative ASK1 blocked the accelerated effects of DKK3 deficiency, while the constitutively active form of ASK1 overcame the inhibitory effects of DKK3 overexpression on HFD-induced metabolic disorders in vivo.

Conclusion: DKK3 functions as a negative regulator of insulin resistance, hepatic steatosis, and associated inflammatory responses, which depends on its inhibitory regulation of ASK1 activity.

Lay Summary: DKK3 expression is decreased in the non-alcoholic fatty liver of humans and mice. Adding DKK3 expression alleviates fatty liver in mice by inhibiting ASK1 activity.
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http://dx.doi.org/10.1016/j.jhep.2016.03.008DOI Listing
July 2016

Hepatocyte TRAF3 promotes liver steatosis and systemic insulin resistance through targeting TAK1-dependent signalling.

Nat Commun 2016 Feb 17;7:10592. Epub 2016 Feb 17.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and a systemic pro-inflammatory response. Here we show that tumour necrosis factor receptor-associated factor 3 (TRAF3) is upregulated in mouse and human livers with hepatic steatosis. After 24 weeks on a high-fat diet (HFD), obesity, insulin resistance, hepatic steatosis and inflammatory responses are significantly ameliorated in liver-specific TRAF3-knockout mice, but exacerbated in transgenic mice overexpressing TRAF3 in hepatocytes. The detrimental effects of TRAF3 on hepatic steatosis and related pathologies are confirmed in ob/ob mice. We further show that in response to HFD, hepatocyte TRAF3 binds to TGF-β-activated kinase 1 (TAK1) to induce TAK1 ubiquitination and subsequent autophosphorylation, thereby enhancing the activation of downstream IKKβ-NF-κB and MKK-JNK-IRS1(307) signalling cascades, while disrupting AKT-GSK3β/FOXO1 signalling. The TRAF3-TAK1 interaction and TAK1 ubiquitination are indispensable for TRAF3-regulated hepatic steatosis. In conclusion, hepatocyte TRAF3 promotes HFD-induced or genetic hepatic steatosis in a TAK1-dependent manner.
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http://dx.doi.org/10.1038/ncomms10592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757796PMC
February 2016

The long noncoding RNA Gm15055 represses Hoxa gene expression by recruiting PRC2 to the gene cluster.

Nucleic Acids Res 2016 Apr 28;44(6):2613-27. Epub 2015 Nov 28.

State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, P.R. China

The Hox genes encode transcription factors that determine embryonic pattern formation. In embryonic stem cells, the Hox genes are silenced by PRC2. Recent studies have reported a role for long noncoding RNAs in PRC2 recruitment in vertebrates. However, little is known about how PRC2 is recruited to the Hox genes in ESCs. Here, we used stable knockdown and knockout strategies to characterize the function of the long noncoding RNAGm15055 in the regulation of Hoxa genes in mouse ESCs. We found that Gm15055 is highly expressed in mESCs and its expression is maintained by OCT4.Gm15055 represses Hoxa gene expression by recruiting PRC2 to the cluster and maintaining the H3K27me3 modification on Hoxa promoters. A chromosome conformation capture assay revealed the close physical association of the Gm15055 locus to multiple sites at the Hoxa gene cluster in mESCs, which may facilitate the in cis targeting of Gm15055RNA to the Hoxa genes. Furthermore, an OCT4-responsive positive cis-regulatory element is found in the Gm15055 gene locus, which potentially regulates both Gm15055 itself and the Hoxa gene activation. This study suggests how PRC2 is recruited to the Hoxa locus in mESCs, and implies an elaborate mechanism for Hoxa gene regulation in mESCs.
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http://dx.doi.org/10.1093/nar/gkv1315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824075PMC
April 2016

Targeting TRAF3 signaling protects against hepatic ischemia/reperfusions injury.

J Hepatol 2016 Jan 31;64(1):146-59. Epub 2015 Aug 31.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, China. Electronic address:

Background & Aims: The hallmarks of hepatic ischemia/reperfusion (I/R) injury, a common clinical problem that occurs during liver surgical procedures, include severe cell death and inflammatory responses that contribute to early graft failure and a higher incidence of organ rejection. Unfortunately, effective therapeutic strategies are limited. Tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 3 transduces apoptosis and/or inflammation-related signaling pathways to regulate cell survival and cytokine production. However, the role of TRAF3 in hepatic I/R-induced liver damage remains unknown.

Methods: Hepatocyte- or myeloid cell-specific TRAF3 knockdown or transgenic mice were subjected to an I/R model in vivo, and in vitro experiments were performed by treating primary hepatocytes from these mice with hypoxia/reoxygenation stimulation. The function of TRAF3 in I/R-induced liver damage and the potential underlying mechanisms were investigated through various phenotypic analyses and biological approaches.

Results: Hepatocyte-specific, but not myeloid cell-specific, TRAF3 deficiency reduced cell death, inflammatory cell infiltration, and cytokine production in both in vivo and in vitro hepatic I/R models, whereas hepatic TRAF3 overexpression resulted in the opposite effects. Mechanistically, TRAF3 directly binds to TAK1, which enhances the activation of the downstream NF-κB and JNK pathways. Importantly, inhibition of TAK1 almost completely reversed the TRAF3 overexpression-mediated exacerbation of I/R injury.

Conclusions: TRAF3 is a novel hepatic I/R mediator that promotes liver damage and inflammation via TAK1-dependent activation of the JNK and NF-κB pathways. Inhibition of hepatic TRAF3 may represent a promising approach to protect the liver against I/R injury-related diseases.
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http://dx.doi.org/10.1016/j.jhep.2015.08.021DOI Listing
January 2016

Oncostatin M Confers Neuroprotection against Ischemic Stroke.

J Neurosci 2015 Aug;35(34):12047-62

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China, Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, PR China

Unlabelled: Cell-surface receptors provide potential targets for the translation of bench-side findings into therapeutic strategies; however, this approach for the treatment of stroke is disappointing, at least partially due to an incomplete understanding of the targeted factors. Previous studies of oncostatin M (OSM), a member of the gp130 cytokine family, have been limited, as mouse models alone may not strongly resemble the human condition enough. In addition, the precise function of OSM in the CNS remains unclear. Here, we report that human OSM is neuroprotective in vivo and in vitro by recruiting OSMRβ in the setting of ischemic stroke. Using gain- and loss-of-function approaches, we demonstrated that decreased neuronal OSMRβ expression results in deteriorated stroke outcomes but that OSMRβ overexpression in neurons is cerebroprotective. Moreover, administering recombinant human OSM to mice before the onset of I/R showed that human OSM can be protective in rodent models of ischemic stroke. Mechanistically, OSM/OSMRβ activate the JAK2/STAT3 prosurvival signaling pathway. Collectively, these data support that human OSM may represent a promising drug candidate for stroke treatment.

Significance Statement: OSM, a member of the gp130 cytokine family, regulates neuronal function and survival. OSM engages a second receptor, either LIFRα or OSMRβ, before recruiting gp130. However, it is not clear whether OSM/OSMRβ signaling is involved in neuroprotection in the setting of ischemic stroke. Recent studies show that, compared with mouse disease models, the OSM receptor system in rats more closely resembles that in humans. In the present study, we use genetic manipulations of OSMRβ in both mouse and rat stroke models to demonstrate that OSMRβ in neurons is critical for neuronal survival during cerebral ischemic/reperfusion. Interestingly, administration of human OSM also leads to improved stroke outcomes. Therefore, OSM may represent a promising drug candidate for stroke treatment.
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http://dx.doi.org/10.1523/JNEUROSCI.1800-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705457PMC
August 2015

Neuron-Specific Tumor Necrosis Factor Receptor-Associated Factor 3 Is a Central Regulator of Neuronal Death in Acute Ischemic Stroke.

Hypertension 2015 Sep 27;66(3):604-16. Epub 2015 Jul 27.

From the Department of Cardiology, Renmin Hospital (J.G., S.G., X.-J.Z., P.Z., G.-N.Z., Y.Z., A.Z., M.X., H.L.), Animal Experiment Center/Animal Biosafety Level-III Laboratory (J.G., S.G., X.-J.Z., P.Z., G.-N.Z., Y.Z., A.Z., M.X., H.L.), and College of Life Sciences (X.-F.Z.), Wuhan University, Wuhan, China; Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China (Z.-Z.L.); National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (Z.-Z.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (L.G.).

Neuronal death after ischemic stroke involves multiple pathophysiological events, as well as a complex molecular mechanism. Inhibiting a single therapeutic target that is involved in several ischemic signaling cascades may be a promising strategy for stroke management. Here, we report the versatile biological roles of tumor necrosis factor receptor-associated factor 3 (TRAF3) in ischemic stroke. Using several genetically manipulated mouse strains, we also demonstrated that TRAF3 inhibition can be neuroprotective. TRAF3 expression, which is robustly induced in response to ischemia/reperfusion (I/R) injury, was detected in neurons. Overexpression of TRAF3 in neurons led to aggravated neuronal loss and enlarged infarcts; these effects were reversed in TRAF3-knockout mice. Neuronal TRAF3 also contributed to c-Jun kinase-, nuclear factor κB- and Rac-1-induced neuronal death, inflammation, and oxidative stress. Mechanistically, we showed that TRAF3 interacts with transforming growth factor-β-activated kinase 1 (TAK1) and potentiates phosphorylation and activation of TAK1. Phosphorylated TAK1 sequentially initiated activation of nuclear factor κB, Rac-1/NADPH oxidase, and c-Jun kinase/c-Jun signaling cascades. Using a combination of adenoviruses encoding dominant-negative TAK1 and the TAK1 inhibitor 5Z-7-oxozeaenol, we demonstrated that the TRAF3-mediated activation of ischemic cascades was TAK1-dependent. More importantly, the adverse phenotypes observed in TRAF3-overexpressing mice were completely reversed when the TRAF3-TAK1 interaction was prevented. Therefore, we have shown that TRAF3 is a central regulator of ischemic pathways, including nuclear factor κB, Rac-1, and c-Jun kinase signaling, via its interaction with and activation of TAK1. Furthermore, certain components of the TRAF3-TAK1 signaling pathway are potentially promising therapeutic targets in ischemic stroke.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05430DOI Listing
September 2015

Exacerbating Pressure Overload-Induced Cardiac Hypertrophy: Novel Role of Adaptor Molecule Src Homology 2-B3.

Hypertension 2015 Sep 22;66(3):571-81. Epub 2015 Jun 22.

From the Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.Z., J.F., X.W.); Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.); and Cardiovascular Research Institute of Wuhan University, Wuhan, China (D.-S.J., P.Z., G.-N.Z., X.Z., L.Y., H.L.).

The adaptor protein Src homology 2-B3 (SH2B3), which belongs to a subfamily of Src homology 2 proteins, is a broad inhibitor of growth factors and cytokine signaling in hematopoietic cells. However, the role of SH2B3 in nonhematopoietic systems, particularly cardiomyocytes, has not been defined. In this study, we observed noticeable increase in SH2B3 protein expression during pathological cardiac remodeling in both humans and rodents. Follow-up in vitro gain- and loss-of-function studies suggested that SH2B3 promotes the cardiomyocyte hypertrophy response. Consistent with the cell phenotype, SH2B3 knockout (SH2B3(-/-)) mice exhibited attenuated cardiac remodeling with preserved cardiac function after chronic pressure overload. Conversely, cardiac-specific SH2B3 overexpression aggravated pressure overload-triggered cardiac hypertrophy, fibrosis, and dysfunction. Mechanistically, SH2B3 accelerates and exacerbates cardiac remodeling through the activation of focal adhesion kinase, which, in turn, activates the prohypertrophic downstream phosphoinositide 3-kinase-AKT-mammalian target of rapamycin/glycogen synthase kinase 3β signaling pathway. Finally, we generated a novel SH2B3 knockout rat line and further confirmed the protective effects of SH2B3 deficiency on cardiac remodeling across species. Collectively, our data indicate that SH2B3 functions as a novel and effective modulator of cardiac remodeling and failure.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05183DOI Listing
September 2015

Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy.

Hypertension 2015 Aug 1;66(2):356-67. Epub 2015 Jun 1.

From the Department of Cardiology, Renmin Hospital (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., H.L.), Cardiovascular Research Institute (X.J., K.-Q.D., D.-S.J., P.Z., G.-N.Z., X.Z., H.L.), and College of Life Sciences (X.-F.Z., G.-N.Z.), Wuhan University, Wuhan, PR China; Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China (Y.L.); and Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China (L.G.).

Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways. Here, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II- or phenylephrine-induced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli. This interaction between TRAF3 and TBK1 further activated AKT signaling, which ultimately promoted the development of cardiac hypertrophy. Our findings not only reveal a key role of TRAF3 in regulating the hypertrophic response but also uncover TRAF3-TBK1-AKT as a novel signaling pathway in the development of cardiac hypertrophy and heart failure. This pathway may represent a potential therapeutic target for this pathological process.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05469DOI Listing
August 2015

CTCF controls HOXA cluster silencing and mediates PRC2-repressive higher-order chromatin structure in NT2/D1 cells.

Mol Cell Biol 2014 Oct 18;34(20):3867-79. Epub 2014 Aug 18.

State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.

HOX cluster genes are activated sequentially in their positional order along the chromosome during vertebrate development. This phenomenon, known as temporal colinearity, depends on transcriptional silencing of 5' HOX genes. Chromatin looping was recently identified as a conserved feature of silent HOX clusters, with CCCTC-binding factor (CTCF) binding sites located at the loop bases. However, the potential contribution of CTCF to HOX cluster silencing and the underlying mechanism have not been established. Here, we demonstrate that the HOXA locus is organized by CTCF into chromatin loops and that CTCF depletion causes significantly enhanced activation of HOXA3 to -A7, -A9 to -A11, and -A13 in response to retinoic acid, with the highest effect observed for HOXA9. Our subsequent analyses revealed that CTCF facilitates the stabilization of Polycomb repressive complex 2 (PRC2) and trimethylated lysine 27 of histone H3 (H3K27me3) at the human HOXA locus. Our results reveal that CTCF functions as a controller of HOXA cluster silencing and mediates PRC2-repressive higher-order chromatin structure.
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http://dx.doi.org/10.1128/MCB.00567-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187707PMC
October 2014

Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease.

Biochim Biophys Acta 2015 Feb 5;1852(2):365-78. Epub 2014 May 5.

Department of Cardiology, Renmin Hospital of Wuhan University Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University Wuhan 430060, China. Electronic address:

The interferon-regulatory factor (IRF) family comprises nine members in mammals. Although this transcription factor family was originally thought to function primarily in the immune system, contributing to both the innate immune response and the development of immune cells, recent advances have revealed that IRFs plays critical roles in other biological processes, such as metabolism. Accordingly, abnormalities in the expression and/or function of IRFs have increasingly been linked to disease. Herein, we provide an update on the recent progress regarding the regulation of immune responses and immune cell development associated with IRFs. Additionally, we discuss the relationships between IRFs and immunity, metabolism, and disease, with a particular focus on the role of IRFs as stress sensors. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
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http://dx.doi.org/10.1016/j.bbadis.2014.04.030DOI Listing
February 2015

The AT-rich DNA-binding protein SATB2 promotes expression and physical association of human (G)γ- and (A)γ-globin genes.

J Biol Chem 2012 Aug 23;287(36):30641-52. Epub 2012 Jul 23.

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, PR China.

Matrix attachment region (MAR)-binding protein (MARBP) has profound influence on gene transcriptional control by tethering genes to the nuclear scaffold. MARBP SATB2 is recently known as a versatile regulator functioning in the differentiation of multiple cell types including embryonic stem cells, osteoblasts and immunocytes. Roles of SATB2 in erythroid cells and its working mechanism in orchestrating target gene expression are largely unexplored. We show here that SATB2 is expressed in erythroid cells and activates γ-globin genes by binding to MARs in their promoters and recruiting histone acetylase PCAF. Further analysis in higher-order chromatin structure shows that SATB2 affects physical proximity of human (G)γ- and (A)γ-globin promoters via self-association. We also found that SATB2 interacts with SATB1, which specifically activates ε-globin gene expression. Our results establish SATB2 as a novel γ-globin gene regulator and provide a glimpse of the differential and cooperative roles of SATB family proteins in modulating clustered genes transcription and mediating higher-order chromatin structures.
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http://dx.doi.org/10.1074/jbc.M112.355271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436309PMC
August 2012

SIRT1 deacetylates SATB1 to facilitate MAR HS2-MAR ε interaction and promote ε-globin expression.

Nucleic Acids Res 2012 Jun 10;40(11):4804-15. Epub 2012 Feb 10.

National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.

The higher order chromatin structure has recently been revealed as a critical new layer of gene transcriptional control. Changes in higher order chromatin structures were shown to correlate with the availability of transcriptional factors and/or MAR (matrix attachment region) binding proteins, which tether genomic DNA to the nuclear matrix. How posttranslational modification to these protein organizers may affect higher order chromatin structure still pending experimental investigation. The type III histone deacetylase silent mating type information regulator 2, S. cerevisiae, homolog 1 (SIRT1) participates in many physiological processes through targeting both histone and transcriptional factors. We show that MAR binding protein SATB1, which mediates chromatin looping in cytokine, MHC-I and β-globin gene loci, as a new type of SIRT1 substrate. SIRT1 expression increased accompanying erythroid differentiation and the strengthening of β-globin cluster higher order chromatin structure, while knockdown of SIRT1 in erythroid k562 cells weakened the long-range interaction between two SATB1 binding sites in the β-globin locus, MAR(HS2) and MAR(ε). We also show that SIRT1 activity significantly affects ε-globin gene expression in a SATB1-dependent manner and that knockdown of SIRT1 largely blocks ε-globin gene activation during erythroid differentiation. Our work proposes that SIRT1 orchestrates changes in higher order chromatin structure during erythropoiesis, and reveals the dynamic higher order chromatin structure regulation at posttranslational modification level.
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http://dx.doi.org/10.1093/nar/gks064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367170PMC
June 2012
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