Long non-coding RNA H19 contributes to wound healing of diabetic foot ulcer

in Journal of Molecular Endocrinology
View More View Less
  • 1 Department of Endocrinology, The Fourth Hospital of Harbin Medical University, Harbin, People’s Republic of China
  • 2 Comprehensive Second Department, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
  • 3 School of Life Science and Technology, Harbin Institute of Technology
  • 4 Department of Laboratory Medicine, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China
  • 5 Department of Endocrinology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China

Correspondence should be addressed to A Zhai or C Bi: aixiazhai@126.com or bichanglongdr@163.com

*(B Li and Y Zhou contributed equally to this work)

Restricted access

Diabetic foot ulcer (DFU) is a chronic and non-healing complication of diabetes that leads to high hospital costs and, in extreme cases, to amputation. Recent studies have reported that long non-coding RNAs (lncRNAs) are linked to various diabetes-related symptoms. Thus, we aim to explore the role of lncRNA H19 in the wound healing process following DFU. Fibroblasts were isolated from the ulcer margin tissues of DFU patients, with the expression of lncRNA H19, connective tissue growth factor (CTGF) or serum response factor (SRF) altered by lentivirus infection. Next, rat models of DFU induced by high glucose and lipid diet were established, which was also infected with the corresponding lentivirus. The interaction among lncRNA H19, SRF and CTGF was determined. Afterward, cell proliferation and apoptosis, angiogenesis, ECM remodeling and wound healing in DFU tissues were evaluated to explore the effects of lncRNA H19/SRF/CTGF and MAPK signaling pathway on DFU. CTGF was poorly expressed in ulcer tissues from DFU rats and patients. CTGF overexpression was shown to activate the MAPK signaling pathway to promote cell proliferation, ECM remodeling, angiogenesis and wound healing while inhibiting cell apoptosis. lncRNA H19 was validated to elevate CTGF expression by recruiting SRF to the promoter region of CTGF, thus accelerating cell proliferation, ECM remodeling and wound healing while repressing cell apoptosis. Furthermore, MAPK signaling pathway activation is confirmed to be the underlying mechanism behind lncRNA H19/CTGF/SRF-induced results. Thus, lncRNA H19 accelerated wound healing in DFU through elevation of CTGF and activation of the MAPK signaling pathway.

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 296 296 200
Full Text Views 23 23 15
PDF Downloads 17 17 11
  • Armstrong DG, Boulton AJM & Bus SA 2017 Diabetic foot ulcers and their recurrence. New England Journal of Medicine 376 23672375. (https://doi.org/10.1056/NEJMra1615439)

    • Search Google Scholar
    • Export Citation
  • Arthur JS & Ley SC 2013 Mitogen-activated protein kinases in innate immunity. Nature Reviews: Immunology 13 679692. (https://doi.org/10.1038/nri3495)

    • Search Google Scholar
    • Export Citation
  • Baelde HJ, Eikmans M, Lappin DW, Doran PP, Hohenadel D, Brinkkoetter PT, van der Woude FJ, Waldherr R, Rabelink TJ, de Heer E, 2007 Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss. Kidney International 71 637645. (https://doi.org/10.1038/sj.ki.5002101)

    • Search Google Scholar
    • Export Citation
  • Ball DK, Rachfal AW, Kemper SA & Brigstock DR 2003 The heparin-binding 10 kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion. Journal of Endocrinology 176 R1R7. (https://doi.org/10.1677/joe.0.176r001)

    • Search Google Scholar
    • Export Citation
  • Barnes CP, Sell SA, Boland ED, Simpson DG & Bowlin GL 2007 Nanofiber technology: designing the next generation of tissue engineering scaffolds. Advanced Drug Delivery Reviews 59 14131433. (https://doi.org/10.1016/j.addr.2007.04.022)

    • Search Google Scholar
    • Export Citation
  • Blumberg SN, Berger A, Hwang L, Pastar I, Warren SM & Chen W 2012 The role of stem cells in the treatment of diabetic foot ulcers. Diabetes Research and Clinical Practice 96 19. (https://doi.org/10.1016/j.diabres.2011.10.032)

    • Search Google Scholar
    • Export Citation
  • Chai J, Norng M, Tarnawski AS & Chow J 2007 A critical role of serum response factor in myofibroblast differentiation during experimental oesophageal ulcer healing in rats. Gut 56 621630. (https://doi.org/10.1136/gut.2006.106674)

    • Search Google Scholar
    • Export Citation
  • Colecchia D, Strambi A, Sanzone S, Iavarone C, Rossi M, Dall’Armi C, Piccioni F, Verrotti di Pianella A & Chiariello M 2012 MAPK15/ERK8 stimulates autophagy by interacting with LC3 and GABARAP proteins. Autophagy 8 17241740. (https://doi.org/10.4161/auto.21857)

    • Search Google Scholar
    • Export Citation
  • Dumville JC, Soares MO, O’Meara S & Cullum N 2012 Systematic review and mixed treatment comparison: dressings to heal diabetic foot ulcers. Diabetologia 55 19021910. (https://doi.org/10.1007/s00125-012-2558-5)

    • Search Google Scholar
    • Export Citation
  • Elliott CG, Wang J, Walker JT, Michelsons S, Dunmore-Buyze J, Drangova M, Leask A & Hamilton DW 2019 Periostin and CCN2 scaffolds promote the wound healing response in the skin of diabetic mice. Tissue Engineering. Part A 25 13261339. (https://doi.org/10.1089/ten.TEA.2018.0268)

    • Search Google Scholar
    • Export Citation
  • Fan W, Peng Y, Liang Z, Yang Y & Zhang J 2019 A negative feedback loop of H19/miR-675/EGR1 is involved in diabetic nephropathy by downregulating the expression of the vitamin D receptor. Journal of Cellular Physiology 234 1750517513. (https://doi.org/10.1002/jcp.28373)

    • Search Google Scholar
    • Export Citation
  • Frangogiannis NG 2012 Matricellular proteins in cardiac adaptation and disease. Physiological Reviews 92 635688. (https://doi.org/10.1152/physrev.00008.2011)

    • Search Google Scholar
    • Export Citation
  • Gan J, Liu C, Li H, Wang S, Wang Z, Kang Z, Huang Z, Zhang J, Wang C, Lv D, 2019 Accelerated wound healing in diabetes by reprogramming the macrophages with particle-induced clustering of the mannose receptors. Biomaterials 219 119340. (https://doi.org/10.1016/j.biomaterials.2019.119340)

    • Search Google Scholar
    • Export Citation
  • Goldberga I, Li R & Duer MJ 2018 Collagen structure-function relationships from solid-state NMR spectroscopy. Accounts of Chemical Research 51 16211629. (https://doi.org/10.1021/acs.accounts.8b00092)

    • Search Google Scholar
    • Export Citation
  • Goldin A, Beckman JA, Schmidt AM & Creager MA 2006 Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114 597605. (https://doi.org/10.1161/CIRCULATIONAHA.106.621854)

    • Search Google Scholar
    • Export Citation
  • Goodson EJ 2016 Earl Wiley Renfroe: man of fortitude and orthodontist extraordinaire. American Journal of Orthodontics and Dentofacial Orthopedics 150 217219. (https://doi.org/10.1016/j.ajodo.2016.05.001)

    • Search Google Scholar
    • Export Citation
  • Goyal N, Tiwary S, Kesharwani D & Datta M 2019 Long non-coding RNA H19 inhibition promotes hyperglycemia in mice by upregulating hepatic FoxO1 levels and promoting gluconeogenesis. Journal of Molecular Medicine 97 115126. (https://doi.org/10.1007/s00109-018-1718-6)

    • Search Google Scholar
    • Export Citation
  • Guo JR, Yin L, Chen YQ, Jin XJ, Zhou X, Zhu NN, Liu XQ, Wei HW & Duan LS 2018 Autologous blood transfusion augments impaired wound healing in diabetic mice by enhancing lncRNA H19 expression via the HIF-1α signaling pathway. Cell Communication and Signaling 16 84. (https://doi.org/10.1186/s12964-018-0290-6)

    • Search Google Scholar
    • Export Citation
  • Hall-Glenn F, De Young RA, Huang BL, van Handel B, Hofmann JJ, Chen TT, Choi A, Ong JR, Benya PD, Mikkola H, 2012 CCN2/connective tissue growth factor is essential for pericyte adhesion and endothelial basement membrane formation during angiogenesis. PLoS ONE 7 e30562. (https://doi.org/10.1371/journal.pone.0030562)

    • Search Google Scholar
    • Export Citation
  • He SH, Wei AY, Yang Y, Hu YW, Luo XG, Liu Y & Zhang T 2012 Reduced expression of myocardin and serum response factor in the cavernous tissue of diabetic rats. Andrologia 44 (Supplement 1) 518522. (https://doi.org/10.1111/j.1439-0272.2011.01218.x)

    • Search Google Scholar
    • Export Citation
  • Henshaw FR, Boughton P, Lo L, McLennan SV & Twigg SM 2015 Topically applied connective tissue growth factor/CCN2 improves diabetic preclinical cutaneous wound healing: potential role for CTGF in human diabetic foot ulcer healing. Journal of Diabetes Research 2015 236238. (https://doi.org/10.1155/2015/236238)

    • Search Google Scholar
    • Export Citation
  • Hon CC, Ramilowski JA, Harshbarger J, Bertin N, Rackham OJ, Gough J, Denisenko E, Schmeier S, Poulsen TM, Severin J, 2017 An atlas of human long non-coding RNAs with accurate 5′ ends. Nature 543 199204. (https://doi.org/10.1038/nature21374)

    • Search Google Scholar
    • Export Citation
  • Hou B, Cai W, Chen T, Zhang Z, Gong H, Yang W & Qiu L 2020 Vaccarin hastens wound healing by promoting angiogenesis via activation of MAPK/ERK and PI3K/AKT signaling pathways in vivo. Acta Cirurgica Brasileira 34 e201901202. (https://doi.org/10.1590/s0102-865020190120000002)

    • Search Google Scholar
    • Export Citation
  • Huang ZW, Tian LH, Yang B & Guo RM 2017 Long noncoding RNA H19 acts as a competing endogenous RNA to mediate CTGF expression by sponging miR-455 in cardiac fibrosis. DNA and Cell Biology 36 759766. (https://doi.org/10.1089/dna.2017.3799)

    • Search Google Scholar
    • Export Citation
  • Hunt KJ, Jaffa MA, Garrett SM, Luttrell DK, Lipson KE, Lopes-Virella MF, Luttrell LM, Jaffa AA & Investigators V 2018 Plasma connective tissue growth factor (CTGF/CCN2) levels predict myocardial infarction in the veterans affairs diabetes trial (VADT) cohort. Diabetes Care 41 840846. (https://doi.org/10.2337/dc17-2083)

    • Search Google Scholar
    • Export Citation
  • Jin W, Goldfine AB, Boes T, Henry RR, Ciaraldi TP, Kim EY, Emecan M, Fitzpatrick C, Sen A, Shah A, 2011 Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance. Journal of Clinical Investigation 121 918929. (https://doi.org/10.1172/JCI41940)

    • Search Google Scholar
    • Export Citation
  • Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE & Weibel S 2015 Hyperbaric oxygen therapy for chronic wounds. Cochrane Database of Systematic Reviews 6 CD004123. (https://doi.org/10.1002/14651858.CD004123.pub4)

    • Search Google Scholar
    • Export Citation
  • Lanna A, Gomes DC, Muller-Durovic B, McDonnell T, Escors D, Gilroy DW, Lee JH, Karin M & Akbar AN 2017 A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nature Immunology 18 354363. (https://doi.org/10.1038/ni.3665)

    • Search Google Scholar
    • Export Citation
  • Lawrence MC, Jivan A, Shao C, Duan L, Goad D, Zaganjor E, Osborne J, McGlynn K, Stippec S, Earnest S, 2008 The roles of MAPKs in disease. Cell Research 18 436442. (https://doi.org/10.1038/cr.2008.37)

    • Search Google Scholar
    • Export Citation
  • Leask A 2010 Getting to the heart of the matter: CCN2 plays a role in cardiomyocyte hypertrophy. Journal of Cell Communication and Signaling 4 7374. (https://doi.org/10.1007/s12079-009-0061-7)

    • Search Google Scholar
    • Export Citation
  • Li B, Luan S, Chen J, Zhou Y, Wang T, Li Z, Fu Y, Zhai A & Bi C 2020 The MSC-derived exosomal lncRNA H19 promotes wound healing in diabetic foot ulcers by upregulating PTEN via microRNA-152-3p. Molecular Therapy: Nucleic Acids 19 814826. (https://doi.org/10.1016/j.omtn.2019.11.034)

    • Search Google Scholar
    • Export Citation
  • Liu F, Chen WW, Li Y, Zhang JQ & Zheng QB 2018 MiR-6836-3p promotes proliferation of hypertrophic scar fibroblasts by targeting CTGF. European Review for Medical and Pharmacological Sciences 22 40694074. (https://doi.org/10.26355/eurrev_201807_15396)

    • Search Google Scholar
    • Export Citation
  • Loots MA, Lamme EN, Zeegelaar J, Mekkes JR, Bos JD & Middelkoop E 1998 Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. Journal of Investigative Dermatology 111 850857. (https://doi.org/10.1046/j.1523-1747.1998.00381.x)

    • Search Google Scholar
    • Export Citation
  • Luo L, Li J, Liu H, Jian X, Zou Q, Zhao Q, Le Q, Chen H, Gao X & He C 2017 Adiponectin is involved in connective tissue growth factor-induced proliferation, migration and overproduction of the extracellular matrix in keloid fibroblasts. International Journal of Molecular Sciences 18 1044. (https://doi.org/10.3390/ijms18051044)

    • Search Google Scholar
    • Export Citation
  • Mason RM 2013 Fell-Muir lecture: connective tissue growth factor (CCN2) – a pernicious and pleiotropic player in the development of kidney fibrosis. International Journal of Experimental Pathology 94 116. (https://doi.org/10.1111/j.1365-2613.2012.00845.x)

    • Search Google Scholar
    • Export Citation
  • Monteiro-Soares M, Boyko EJ, Ribeiro J, Ribeiro I & Dinis-Ribeiro M 2012 Predictive factors for diabetic foot ulceration: a systematic review. Diabetes/Metabolism Research and Reviews 28 574600. (https://doi.org/10.1002/dmrr.2319)

    • Search Google Scholar
    • Export Citation
  • Moran I, Akerman I, van de Bunt M, Xie R, Benazra M, Nammo T, Arnes L, Nakic N, Garcia-Hurtado J, Rodriguez-Segui S, 2012 Human beta cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metabolism 16 435448. (https://doi.org/10.1016/j.cmet.2012.08.010)

    • Search Google Scholar
    • Export Citation
  • Pi L, Robinson PM, Jorgensen M, Oh SH, Brown AR, Weinreb PH, Trinh TL, Yianni P, Liu C, Leask A, 2015 Connective tissue growth factor and integrin alphavbeta6: a new pair of regulators critical for ductular reaction and biliary fibrosis in mice. Hepatology 61 678691. (https://doi.org/10.1002/hep.27425)

    • Search Google Scholar
    • Export Citation
  • Plantier L, Renaud H, Respaud R, Marchand-Adam S & Crestani B 2016 Transcriptome of cultured lung fibroblasts in idiopathic pulmonary fibrosis: meta-analysis of publically available microarray datasets reveals repression of inflammation and immunity pathways. International Journal of Molecular Sciences 17 2091. (https://doi.org/10.3390/ijms17122091)

    • Search Google Scholar
    • Export Citation
  • Shahbazian H, Yazdanpanah L & Latifi SM 2013 Risk assessment of patients with diabetes for foot ulcers according to risk classification consensus of International Working Group on Diabetic Foot (IWGDF). Pakistan Journal of Medical Sciences 29 730734. (https://doi.org/10.12669/pjms.293.3473)

    • Search Google Scholar
    • Export Citation
  • Sonnylal S, Shi-Wen X, Leoni P, Naff K, Van Pelt CS, Nakamura H, Leask A, Abraham D, Bou-Gharios G & de Crombrugghe B 2010 Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis. Arthritis and Rheumatism 62 15231532. (https://doi.org/10.1002/art.27382)

    • Search Google Scholar
    • Export Citation
  • Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, Little CB, Last K, Farmer PJ, Campbell IK, 2005 ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434 648652. (https://doi.org/10.1038/nature03417)

    • Search Google Scholar
    • Export Citation
  • Tasharrofi B & Ghafouri-Fard SL 2018 Long non-coding RNAs as regulators of the mitogen-activated protein kinase (MAPK) pathway in cancer. Klinicka Onkologie 31 95102. (https://doi.org/10.14735/amko201895)

    • Search Google Scholar
    • Export Citation
  • Thomson SE, McLennan SV, Hennessy A, Boughton P, Bonner J, Zoellner H, Yue DK & Twigg SM 2010 A novel primate model of delayed wound healing in diabetes: dysregulation of connective tissue growth factor. Diabetologia 53 572583. (https://doi.org/10.1007/s00125-009-1610-6)

    • Search Google Scholar
    • Export Citation
  • Turns M 2012 The diabetic foot: an overview for community nurses. British Journal of Community Nursing 17 422, 424427, 430423. (https://doi.org/10.12968/bjcn.2012.17.9.422)

    • Search Google Scholar
    • Export Citation
  • Wagner FW Jr 1981 The dysvascular foot: a system for diagnosis and treatment. Foot and Ankle 2 64122. (https://doi.org/10.1177/107110078100200202)

    • Search Google Scholar
    • Export Citation
  • Wang S, Li B, Li C, Cui W & Miao L 2015 Potential renoprotective agents through inhibiting CTGF/CCN2 in diabetic nephropathy. Journal of Diabetes Research 2015 962383. (https://doi.org/10.1155/2015/962383)

    • Search Google Scholar
    • Export Citation
  • Wang W, Yang C, Wang XY, Zhou LY, Lao GJ, Liu D, Wang C, Hu MD, Zeng TT, Yan L, 2018 MicroRNA-129 and -335 promote diabetic wound healing by inhibiting Sp1-mediated MMP-9 expression. Diabetes 67 16271638. (https://doi.org/10.2337/db17-1238)

    • Search Google Scholar
    • Export Citation
  • Yan B, Tao ZF, Li XM, Zhang H, Yao J & Jiang Q 2014 Aberrant expression of long noncoding RNAs in early diabetic retinopathy. Investigative Ophthalmology and Visual Science 55 941951. (https://doi.org/10.1167/iovs.13-13221)

    • Search Google Scholar
    • Export Citation
  • Yan W, Liu H, Deng X, Jin Y, Wang N & Chu J 2018 Acellular dermal matrix scaffolds coated with connective tissue growth factor accelerate diabetic wound healing by increasing fibronectin through PKC signalling pathway. Journal of Tissue Engineering and Regenerative Medicine 12 e1461e1473. (https://doi.org/10.1002/term.2564)

    • Search Google Scholar
    • Export Citation
  • Yazdanpanah L, Nasiri M & Adarvishi S 2015 Literature review on the management of diabetic foot ulcer. World Journal of Diabetes 6 3753. (https://doi.org/10.4239/wjd.v6.i1.37)

    • Search Google Scholar
    • Export Citation
  • Ye J, Kang Y, Sun X, Ni P, Wu M & Lu S 2017 MicroRNA-155 inhibition promoted wound healing in diabetic rats. International Journal of Lower Extremity Wounds 16 7484. (https://doi.org/10.1177/1534734617706636)

    • Search Google Scholar
    • Export Citation
  • Yosimichi G, Nakanishi T, Nishida T, Hattori T, Takano-Yamamoto T & Takigawa M 2001 CTGF/Hcs24 induces chondrocyte differentiation through a p38 mitogen-activated protein kinase (p38MAPK), and proliferation through a p44/42 MAPK/extracellular-signal regulated kinase (ERK). European Journal of Biochemistry 268 60586065. (https://doi.org/10.1046/j.0014-2956.2001.02553.x)

    • Search Google Scholar
    • Export Citation
  • Zhang B, Zhou KK & Ma JX 2010 Inhibition of connective tissue growth factor overexpression in diabetic retinopathy by SERPINA3K via blocking the WNT/beta-catenin pathway. Diabetes 59 18091816. (https://doi.org/10.2337/db09-1056)

    • Search Google Scholar
    • Export Citation
  • Zhang J, Yang C, Wang C, Liu D, Lao G, Liang Y, Sun K, Luo H, Tan Q, Ren M, 2016 AGE-induced keratinocyte MMP-9 expression is linked to TET2-mediated CpG demethylation. Wound Repair and Regeneration 24 489500. (https://doi.org/10.1111/wrr.12426)

    • Search Google Scholar
    • Export Citation
  • Zhang X, Hong R, Chen W, Xu M & Wang L 2019 The role of long noncoding RNA in major human disease. Bioorganic Chemistry 92 103214. (https://doi.org/10.1016/j.bioorg.2019.103214)

    • Search Google Scholar
    • Export Citation
  • Zhao M, Wang H, Chen J, Xi Y, Wang F, Huo C, Li W, Chu Y, Xu P, Huang Q, 2019 Expression of long non-coding RNA H19 in colorectal cancer patients with type 2 diabetes. Archives of Physiology and Biochemistry [epub]. (https://doi.org/10.1080/13813455.2019.1628068)

    • Search Google Scholar
    • Export Citation
  • Zimprich A, Mroz G, Meyer Zu Reckendorf C, Anastasiadou S, Forstner P, Garrett L, Holter SM, Becker L, Rozman J, Prehn C, 2017 Serum response factor (SRF) ablation interferes with acute stress-associated immediate and long-term coping mechanisms. Molecular Neurobiology 54 82428262. (https://doi.org/10.1007/s12035-016-0300-x)

    • Search Google Scholar
    • Export Citation