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Activating connexin43 gap junctions primes adipose tissue for therapeutic intervention

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3063-3072页

作者： Yi Zhu Na Li Mingyang Huang Xi Chen Yu AAn Jianping Li Shangang Zhao Jan-Bernd Funck Jianhong Cao Zhenyan He Qingzhang Zhu Zhuzhen Zhang Zhao VWang Lin Xu Kevin W.Williams Chien Li Kevin Grove Philipp E.Scherer Touchstone Diabetes Center Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Division of Cardiology Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Division of Hypothalamic Research Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Quantitative Biomedical Research Center Department of Population and Data Sciencesthe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Department of Pediatrics the University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Novo Nordisk Research Center SeattleWA 98109USA Children’s Nutrition Research Center Department of PediatricsBaylor College of MedicineHoustonTX 77030USA Department of Cell Biology the University of Texas Southwestern Medical Center at DallasDallasTX 75390USA

Adipose tissue is a promising target for treating obesity and metabolic ***,pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization,especially in obese *** have previously shown that during cold exposure,connexin43(Cx43)gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple *** reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose *** an adipose tissue-specific Cx43 overexpression mouse model,we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of theβ_(3)-adrenergic receptor agonist Mirabegron and ***,combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced *** light of these findings,we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage ***,Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

关键词： GJA1 Adipose tissue Gap junction connexin43 FGF21 β3-Adrenergic receptor agonist Obesity Type 2 diabetes

connexin43 Modulates X-Ray-Induced Pyroptosis in Human Umbilical Vein Endothelial Cells

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Biomedical and Environmental Sciences 2019年第3期32卷 177-188页

作者： LI Chen TIAN Mei GOU Qiao JIA Yong Rui SU Xu China CDC Key Laboratory of Radiological Protection and Nuclear Emergency National Institute for Radiological Protection Chinese Center for Disease Control and Prevention Medical and Health Analysis Center Peking University

Objective Pyroptosis is an inflammatory form of programmed cell death. This phenomenon has been recently reported to play an important role in radiation-induced normal tissue injury. connexin43(Cx43) is a gap junction protein that regulates cell growth and apoptosis. In this study, we investigated the effect of Cx43 on X-ray-induced pyroptosis in the human umbilical vein endothelial cells(HUVECs). Methods HUVECs, Cx43 overexpression, and Cx43 knockdown strains were irradiated with 10 Gy. Proteins were detected using western blot analysis. Cell pyroptosis was evaluated using the fluorescence-labeled inhibitor of caspase assay(FLICA) and propidium iodide staining through flow cytometry and confocal microscopy. Cell morphology and cytotoxicity were detected by scanning electron microscopy and lactate dehydrogenase release assay, respectively. Results Irradiation with 10 Gy X-ray induced pyroptosis in the HUVECs and reduced Cx43 expression. The pyroptosis in the HUVECs was significantly attenuated by overexpression of Cx43 as it decreased the level of active caspase-1. However, interference of Cx43 expression with si RNA significantly promoted pyroptosis by increasing the active caspase-1 level. Pannexin1(Panx1), a gap junction protein regulates pyroptosis, and its cleaved form is used to evaluate channel opening and active state. The level of cleaved Panx1 in the HUVECs and Cx43 knockdown strains increased in the presence of X-ray, but decreased in the Cx43 overexpression strains. Furthermore, interference of Panx1 with si RNA alleviated the upregulation of pyroptosis caused by Cx43 knockdown. Conclusion Results suggest that single high-dose X-ray irradiation induces pyroptosis in the HUVECs. In addition, Cx43 regulates pyroptosis directly by activating caspase-1 or indirectly by cleaving Panx1.

关键词： X-ray connexin43 HUVECs Pyroptosis

Relationship Between Hematoma Expansion Induced by Hypertension and Hyperglycemia and Blood-brain Barrier Disruption in Mice and Its Possible Mechanism:Role of Aquaporin-4 and connexin43

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Neuroscience Bulletin 2020年第11期36卷 1369-1380页

作者： Heling Chu Zidan Gao Chuyi Huang Jing Dong Yuping Tang Qiang Dong Department of Neurology Huashan HospitalState Key Laboratory of Medical NeurobiologyFudan UniversityShanghai 200040China Department of Neurology North Huashan HospitalFudan UniversityShanghai 201907China Department of Neurology Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004China Department of Neurology Shanghai East HospitalTongji University School of MedicineShanghai 200120China

We aimed to select an optimized hematoma expansion(HE)model and investigate the possible mechanism of blood-brain barrier(BBB)damage in *** results showed that HE occurred in the group with hypertension combined with hyperglycemia(HH-HE)from3 to 72 h after intracerebral hemorrhage;this was accompanied by neurological deficits and hardly influenced the survival *** receiver operating characteristic curve suggested the criterion for this model was hematoma volume expansion≥45.0%.Meanwhile,HH-HE aggravated BBB disruption.A protector of the BBB reduced HH-HE,while a BBB disruptor induced a further ***-4(AQP4)knock-out led to larger hematoma volume and more severe BBB ***,hematoma volume and BBB disruption were reduced by multiple connexin43(Cx43)inhibitors in the wild-type group but not in the AQP4 knock-out *** conclusion,the optimized HE model is induced by hypertension and hyperglycemia with the criterion of hematoma volume expanding≥45.0%.HH-HE leads to BBB disruption,which is dependent on AQP4 and Cx43.

关键词： Intracerebral hemorrhage Hematoma expansion Animal model Blood-brain barrier Aquaporin-4 connexin43

Atorvastatin prevents connexin43 remodeling in hypertrophied left ventricular myocardium of spontaneously hypertensive rats

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Chinese Medical Journal 2007年第21期120卷 1902-1907页

作者： CHEN Hong-juan YAO Lei CHEN Tu-gang YU Min WANG Li-hong CHEN Jun-zhu Department of Cardiology First Affiliated Hospital of Medical College Zhejiang University Hangzhou 310003 China Department of Ultrasonic Diagnosis First Affiliated Hospital of Medical College Zhejiang University Hangzhou 310003 China

Background connexin43 （Cx43） is the predominant gap junction protein in heart and is involved in the control of cell-to-cell communication to modulate the contractility and the electrical coupling of cardiac myocytes. Left ventricular （LV） hypertrophy is accompanied by changes of Cx43 expression. Recent studies have demonstrated that statins reduced cardiac hypertrophy. However, it is unknown whether statins can affect Cx43 expression in hypertrophied left ventricular myocardium. This study was designed to assess the effects of atorvastatin on LV hypertrophy and Cx43 expression in spontaneously hypertensive rats （SHR）. Methods Nine-week old SHRs were randomly divided into two groups. Some received atorvastatin at 30 mg/kg by oral gavage once daily for 8 weeks （SHR-A）; others received vehicle. Age-matched Wistar-Kyoto rats （WKY） received atorvastatin or vehicle for 8 weeks were used as controls. At the end of the experiment, we investigated LV hypertrophy and the expression of Cx43 in LV myocardium in four groups. Cx43 expression was investigated by the methods of Western blotting, immunohistochemistry, and transmission electron microscope. LV hypertrophy was accessed by pathological analysis and plasma brain natriuretic peptide （BNP） level. Results LV hypertrophy was prominent in untreated SHR. In SHR, LV myocardium Cx43 level was upregulated, and the distribution of Cx43 was displaced from their usual locations to other sites at various distances away from the intercalated disks. After atorvastatin treatment, myocardium Cx43 level was reduced in SHR-A, and the distribution of Cx43 gap junction became much regular and confined to intercalated disk. Statins also prevented LV hypertrophy in SHR. Conclusions These results provide novel in vivo evidence for the key role of Cx43 gap junctions in LV hypertrophy and the possible mechanism in anti-hypertrophic effect of statins. Atorvastatin treatment may have beneficial effects on LV hypertrophy in spontaneously hypertensi

关键词： connexin43 atorvastatin rats, spontaneously hypertensive hypertrophy, left ventricular

Effect of cAMP and cGMP on connexin43 Expression in Isolated Human and Bovine Ciliary Epithelium

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American Journal of Molecular Biology 2022年第3期12卷 97-108页

作者： Ning Ma Xiaohong Li Renyi Wu Eye Institute and Affiliated Xiamen Eye Center of Xiamen University School of Medicine Xiamen University Xiamen China Fujian Provincial Key Laboratory of Corneal & Ocular Surface Diseases Xiamen China Shanghai Peace Eye Hospital Shanghai China

The aim of the study was to assess the distribution of connexin43 (Cx43) and connexin40 (Cx40) in human and bovine ciliary bodies. The effect of the second messengers cAMP and cyclic cGMP on Cx43 protein expression was also investigated. Enucleated human eyes (remnant after corneal transplantation) and bovine eyes were used. Tissue preparations of the anterior segments of the eyes have proceeded for immunohistochemical staining with polyclonal antibodies of Cx43 and Cx40. Isolated ciliary bodies of human and bovine eyes were incubated with cAMP analog 8-Bromo-cAMP or the cGMP analog 8-Bromo-cGMP, the expression of Cx43 protein in the tissues was then assessed by Western blot assay. Both in human and bovine ciliary bodies, strong immunoreactivity of Cx43, but not Cx40, was observed predominantly in the apical cytoplasmic portions of the pigment ciliary epithelial cells and non-pigmented ciliary epithelial cells. In human ciliary body both cAMP and cGMP up-regulated Cx43 expression, while in the bovine ciliary body, cGMP increased Cx43 expression but cAMP decreased it. Cx43 is the major component of human and bovine gap junctions in the ciliary epithelium. The regulation on the Cx43 expression by cAMP and cGMP in human and bovine ciliary bodies suggests the possibly different roles of these signal messengers in the intracellular communication.

关键词： Gap Junction connexin43 connexin40 cAMP cGMP Aqueous Humor

connexin43在脑出血后继发性损伤中的作用机制及EMSC移植治疗的研究

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Connexin43在脑出血后继发性损伤中的作用机制及EMSC移植治疗的研...

作者：陆聪江苏大学

学位级别：硕士

目的:探讨缝隙连接蛋白connexin43(Cx43)在脑出血(intracerebral hemorrhage,ICH)后继发性损伤中的作用机制及外胚间充质干细胞(ecto-mesenchymal stem cell,EMSC)移植治疗的效果。方法:1.采用血肿降解产物血红素处理星形胶质细胞(Astrocyte,ASC),建立氧化应激损伤的细胞模型,通过TAT-Gap19封闭Cx43半通道(hemichannel,HC),CBX阻断Cx43细胞间缝隙连接通讯(gap junctional intercellular communication,GJIC),观察对血红素hemin诱导的细胞凋亡和铁死亡的影响,并探讨可能的作用机制。2.采用干扰慢病毒敲降ASC中Cx43表达,观察细胞对hemin诱导的凋亡和铁死亡的敏感性。通过基因集富集分析(gene set enrichment analysis,GSEA),预测Cx43在通道功能之外参与调控细胞凋亡和铁死亡的作用机制和信号通路。3.采用细胞因子白细胞介素-1α(interleukin-1α,IL-1α),肿瘤坏死因子α(tumor necrosis factor,TNF-α)和补体C1q处理ASC建立稳定的A1表型。将EMSC与A1进行共培养,观察EMSC对A1表型的逆转作用。4.建立ICH大鼠模型,将EMSC通过出血同侧的颈内动脉行血管内移植,观察对大鼠神经功能的改善情况,并且通过免疫荧光染色,观察移植细胞的迁移及转归,血肿周边ASC活化及A1表型转化情况,神经元和白质纤维损伤程度。5.采用单细胞转录组测序对体外纯化培养的EMSC进行表征,通过生信分析手段预测EMSC发挥免疫调节作用的可能机制。结果:1.在生理状态下,ASC高表达Cx43,HC处于关闭状态,细胞间通过GJIC形成合胞体样结构,对于维持细胞稳态至关重要。在受到hemin刺激后,ASC发生活化,Cx43下调,HC异常开放,GJIC功能下降,细胞发生凋亡和铁死亡。采用TAT-Gap19封闭Cx43 HC后,ASC对hemin诱导的细胞凋亡和铁死亡抵抗能力增强,而CBX阻断Cx43 GJIC后,ASC对hemin诱导的凋亡和铁死亡敏感性增加。2.采用干扰慢病毒敲降ASC中Cx43表达后,ASC对hemin诱导的细胞凋亡的抵抗能力增强而对hemin诱导的铁死亡的敏感性增加。GSEA分析发现Cx43与Hippo信号通路,铁代谢,脂质过氧化通路,缺氧应激等通路显著相关,提示Cx43在通道功能之外,还可能通过Cx43-Hippo信号通路调控脂质代谢及铁死亡。转录因子调控网络分析提示TEAD3可能参与其中。***在体内外实验中均可以逆转A1表型。EMSC通过血肿同侧的颈内动脉移植可以向损伤区域定向迁移,并可减轻ICH大鼠的脑水肿,改善神经功能。免疫荧光染色结果显示,EMSC移植可以抑制ASC活化及A1表型转化,保护神经元和白质纤维。敲除EMSC中Cx43表达后,EMSC的上述神经保护作用被削弱。免疫荧光共定位观察结果显示移植的EMSC弥散分布于损伤灶周边的脑实质内,但本身并不能分化成神经元或胶质细胞。敲除Cx43的EMSC移植后在血肿环境中无法存活,最终发生坏死崩解并被胶质瘢痕包裹。***的单细胞转录组测序结果显示,EMSC同时表达间充质干细胞和成纤维细胞标志蛋白的一群增殖活跃的细胞。对EMSC的细胞功能相关基因集进行GSVA分析表明EMSC在DNA复制、损伤修复、细胞间紧密连接、TGF-β信号通路相关的基因集中存在富集。结论:***43 GJIC对于维持ASC稳态至关重要,可保护细胞免受凋亡和铁死亡。Cx43 HC在生理状态下处于关闭状态,在受到hemin刺激后出现异常开放,导致细胞膜通透性增高,细胞出现凋亡和铁死亡。在ICH后针对性保护Cx43GJIC和封闭Cx43 HC有助于实现神经保护,减轻继发性氧化应激损伤。***43除了通道功能之外,还可以通过YAP/TEAD3调控细胞表型转化,细胞凋亡和铁死亡。***43具有缝隙连接通道,半通道和基因表达调控等多种功能,参与了ICH后细胞的氧化应激损伤过程。在ICH时,维持ASC中Cx43表达水平并保护GJIC,阻断异常开放的HC,有助于稳定细胞表型,减少细胞凋亡和铁死亡。***活化及A1表型转化在ICH后的继发性损伤中发挥重要作用。EMSC可以通过Cx43依赖的模式抑制ASC活化并逆转A1表型,发挥神经保护作用。TGF-β信号通路可能参与其中。5.通过颈内动脉移植EMSC可以高效的将干细胞送达损伤区域发挥神经保护作用。EMSC移植可以抑制ICH后的ASC活化及A1表型,并减轻脑水肿,保护神经元和白质纤维,这一作用依赖于Cx43的正常表达。且EMSC的Cx

关键词：脑出血星形胶质细胞血红素铁死亡凋亡表型转化 connexin43 缝隙连接半通道

connexin43在幼年小鼠非酒精性脂肪性肝病中的表达分析研究

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Connexin43在幼年小鼠非酒精性脂肪性肝病中的表达分析研究

作者：任笑笑大连医科大学

学位级别：硕士

背景:非酒精性脂肪性肝病(Nonalcoholic fatty liver disease,NAFLD)是指除外长期大量饮酒和其他明确的损肝因素所引起的,以脂质在肝细胞中蓄积为病理改变的肝脏代谢性疾病;也可用来描述NASH发病前期的早期的良性病变;并有可能发展成肝... 详细信息

背景:非酒精性脂肪性肝病(Nonalcoholic fatty liver disease,NAFLD)是指除外长期大量饮酒和其他明确的损肝因素所引起的,以脂质在肝细胞中蓄积为病理改变的肝脏代谢性疾病;也可用来描述NASH发病前期的早期的良性病变;并有可能发展成肝硬化、肝衰竭、肝细胞性肝癌,危害人类的健康。近年来,提出了与代谢相关的脂肪性肝病的概念,即超重/肥胖、2型糖尿病、多种代谢紊乱等为主要病因,其中以肝细胞脂肪变性主要病理特征,并作为其启动因素参与了纤维化的进程。肥胖是NAFLD的独立危险因素,近年来,随着国内外儿童和青少年的超重和肥胖问题日益突出,NAFLD的患病率呈现快速增长趋势。研究表明儿童NAFLD肝脏组织病理与成人不同,汇管区和/或肝细胞之间有不同程度的炎性细胞浸润,伴有肝巨噬细胞增殖,以及周围的纤维组织的增殖。儿童、青少年NAFLD是病理可逆的,阐明MAFLD发病机制并寻找有效的治疗药物显得十分重要。缝隙连接(GJ)是一种位于相邻细胞之间的蛋白质连接通道,由缝隙连接蛋白(connexins)组成,它的主要作用是通过介导相邻细胞之间的信号转导,从而调控细胞的新陈代谢、内环境的稳定、增殖和分裂。各种外源性和内源性的化学物质可以影响肝脏Cx表达和GJIC水平。由于肝Cx结构的变化,会导致GJ的通透性和对通透物质的选择性发生变化,进而导致细胞之间的物质交换和信息传递,导致细胞功能异常。目前,在肝组织中已发现Cx32,Cx26,Cx37,Cx40,Cx43。Cxs是维持肝细胞内环境稳定、细胞分裂和细胞生长和发育过程的关键因素。Cx43在非实质的肝细胞,如星状细胞、库普弗细胞及窦上皮细胞中表达。正常肝细胞中Cx43均匀分布在不同的腺泡区域,定位于细胞膜及细胞质中,以膜为主,有助于膜囊泡的组成。Cx43介导的细胞-细胞耦合允许信号在肝细胞间传播,Cx43的表达可能在正常情况下受到抑制,但在应激环境下,Cx43的表达可能会上调,引起内质网功能障碍和胰岛素抵抗。在肥胖中,Cx43允许有害信号在肝细胞间传播,导致脂肪性肝病和代谢改变。目的:探索Cx43在高脂、高热量饮食诱导幼年小鼠肝病模型肝脏中的表达变化特点,为进一步的干预研究奠定研究基础,探讨幼年小鼠非酒精性肝病中Cx43表达及其与肝细胞脂质沉积、内质网应激、炎症浸润及氧化应激的关系。方法:本实验采用5周龄C57BL/6J(n=24只),随机分为2个对照组,分别饲养高脂饮食(D12492)建立NAFLD模式,饲养正常饮食(D12450)作为对照(CON)。在饲养13周后建立NAFLD模型,对小鼠体重、肝脏净重进行了准确的测定,收集了小鼠血液和肝脏的标本。采用全自动生化分析仪对血糖、血脂、胆固醇、甘油三酯进行检测。采用HE和油红O染色观察肝脏病变程度。免疫组织化学染色检测CX43在小鼠肝脏组织的表达及定位,脂质沉积相关指标CD36,炎症浸润相关指标CD68、F4/80(EMR1)及内质网应激相关指标GRP78、p IRE1的表达。结果:采用全自动生化分析器对血糖、胆固醇、甘油三脂进行测定,以评价代谢指标的改变。与正常对照组比较,NAFLD组小鼠的重量、肝脏净重(P43表达上调,内质网应激的标志物GRP78、IRE1以及巨噬细胞标记物标志物CD68、F4/80和脂质沉积相关指标CD36表达上调(P43在幼年小鼠NAFLD模型中表达上调,Cx43参与并控制脂肪肝中脂质沉积、内质网应激、炎症浸润、氧化应激等病理变化。

关键词：非酒精性脂肪性肝病 connexin43 肝脂肪变性内质网应激肝脏炎症浸润

Relationship between the Expression of connexin43 and Bystander Effect of Suicide Gene Therapy in Ovarian Cancer

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2004年第5期24卷 476-479页

作者：张阿丽王全胜韩志强邬素芳陈刚李军廖国宁卢运萍马丁 Department of Obstetrics and Gynecology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China Department of Nephrology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China

The relationship of connexin43 (Cx43) and bystander effect in ovarian tumor cells in herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy in vitro was explored and the effect of all-trans retinoic acid (RA) on the expression of Cx43 and bystander effect investigated. The Cx43 expression was detected by flowcytometry, Western blot, and immunofluorescence in two ovarian tumor cell lines OVCAR3, CaOV3 before and after RA treatment. Bystander effect was determined by the cells growth inhibitory rate with methyl thiazolyl tetrazolium. Following exposure to ganciclovir, there was much greater bystander killing in OVCAR3 than that in CaOV3 (P43 was detected in OVCAR3 by flowcytometry and Western blot, but it could not be detected in CaOV3. The expression of Cx43 in both cell lines could be induced by RA. Immunofluoresence staining showed that Cx43 protein of OVCAR3 was located on membrane surface, whereas CaOV3 in cytoplasm. RA could not change the location of Cx43 protein in both cell lines. There is relationship between Cx43 expression and HSV-TK/GCV bystander effect. HSV-TK/GCV bystander effect can be enhanced by RA in ovarian cancer.

关键词： gene therapy ovarian neoplasms connexin43 retinoic acid

Changes in Phosphorylation of connexin43 in Rats during Acute Myocardial Hypoxia and Effects of Antiarrhythmic Peptide on the Phosphorylation

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2007年第3期27卷 241-244页

作者：王荣张存泰阮燕菲刘念王琳 Department of Cardiology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

In order to confirm the hypothesis that during acute hypoxia, the antiarrhythmic peptide (AAP10) could improve conductance by changing the phosphorylation state of connexin43 (Cx43), isolated perfused rat hearts were randomly divided into three groups: control, hypoxia and AAP10 (n=9 in each group). The change in Cx43 phosphorylation was tested by Western-blot; the distribu- tion of Cx43 was observed by confocal immunofluorescence microscopy. Western-blot analysis re- vealed that the expression of total Cx43 protein was significantly decreased during acute hypoxia, while nonphosphorylated Cx43 (NP-Cx43) was unchanged. AAP10 could increase the expression of total Cx43 protein, but had no effects on the NP-Cx43 protein. Immunofluorescence study showed that during acute hypoxia, both total Cx43 and NP-Cx43 proteins were greatly decreased, while AAP10 only increased the expression of total Cx43 protein, but had no effect of the NP-Cx43 protein expression. These findings suggested that the decrease of intercellular communication may be associ- ated with the reduction of phosphorylated Cx43 (p-Cx43) and translocation of NP-Cx43 from the surface of gap junction into intracellular pools during acute hypoxia. AAP10 can improve intercelluar communication by enhancing phosphorylation of Cx43.

关键词： hypoxia connexin43 phosphorylation antiarrhythmic peptide