miR-21 promotes fibrosis in an acute cardiac allograft transplantation model

被引:61
作者
Gupta, Shashi Kumar [1 ]
Itagaki, Ryo [2 ]
Zheng, Xiang [3 ]
Batkai, Sandor [1 ]
Thum, Sabrina [1 ]
Ahmad, Fareed [4 ]
Van Aelst, Lucas N. [5 ]
Sharma, Amit [6 ]
Piccoli, Maria-Teresa [1 ]
Weinberger, Florian
Fiedler, Jan [1 ]
Heuser, Michael [6 ]
Heymans, Stephane [5 ,7 ]
Falk, Christine S. [8 ,9 ]
Foerster, Reinhold [3 ]
Schrepfer, Sonja [2 ]
Thum, Thomas [1 ,10 ,11 ]
机构
[1] Hannover Med Sch, IMTTS, OE 8886, Carl Neuberg Str 1, D-30625 Hannover, Germany
[2] Univ Heart Ctr, TSI Lab, Hamburg, Germany
[3] Hannover Med Sch, Inst Immunol, D-30625 Hannover, Germany
[4] Hannover Med Sch, Clin Immunol & Rheumatol, D-30625 Hannover, Germany
[5] Univ Leuven, Dept Cardiovasc Sci, Leuven, Belgium
[6] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, D-30625 Hannover, Germany
[7] Maastricht Univ, Dept Cardiol, Fac Hlth Med & Life Sci, NL-6200 MD Maastricht, Netherlands
[8] Hannover Med Sch, Transplant Immunol Integrated Res & Treatment Ctr, D-30625 Hannover, Germany
[9] German Ctr Infect Res DZIF, Braunschweig, Germany
[10] Hannover Med Sch, REBIRTH Excellence Cluster, D-30625 Hannover, Germany
[11] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England
关键词
MiRNA-21; Fibrosis; Cardiac transplantation; Fibrocyte; Allograft; AUTOREGULATORY LOOP; CELLS; MICRORNA-21; PROTEIN-1; INDUCTION; HEARTS; AP-1;
D O I
10.1093/cvr/cvw030
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aims Cardiac transplantation is the only curative therapy for end-stage heart failure. Fibrosis is one of the major causes for impaired function of cardiac allografts. MicroRNAs, a class of small non-coding RNAs, play a critical role in the development of cardiovascular disease, but the role of microRNAs in cardiac allograft failure is not well understood. Methods and results To uncover a role of microRNAs during cardiac graft fibrosis, we generated global microRNA profiles in allogeneic (BALB/c in C57BL/6N) and isogeneic (C57BL/6N in C57BL/6N) murine hearts after transplantation. miR-21 together with cardiac fibrosis was increased in cardiac allografts compared with isografts. Likewise, patients with cardiac rejection after heart transplantation showed increased cardiac miR-21 levels. miR-21 was induced upon treatment with IL-6 in a monocyte cell line. Overexpression of miR-21 in this monocyte cell line activated a fibrotic gene programme and promoted monocyte-to-fibrocyte transition together with activation of chemokine (C-C) motif ligand 2 (monocyte chemoattractant protein 1) via the phosphatase and tensin homologue/activator protein 1 regulatory axis. In vivo, both genetic and pharmacological inhibition of miR-21 successfully reduced fibrosis and fibrocyte accumulation in cardiac allografts. Conclusion Thus, inhibition of miR-21 is a novel strategy to target fibrosis development in cardiac allografts.
引用
收藏
页码:215 / 226
页数:12
相关论文
共 28 条
  • [1] MicroRNA expression profiles predictive of human renal allograft status
    Anglicheau, Dany
    Sharma, Vijay K.
    Ding, Ruchuang
    Hummel, Aurelie
    Snopkowski, Catherine
    Dadhania, Darshana
    Seshan, Surya V.
    Suthanthiran, Manikkam
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (13) : 5330 - 5335
  • [2] MicroRNA-21 Promotes Fibrosis of the Kidney by Silencing Metabolic Pathways
    Chau, B. Nelson
    Xin, Cuiyan
    Hartner, Jochen
    Ren, Shuyu
    Castano, Ana P.
    Linn, Geoffrey
    Li, Jian
    Tran, Phong T.
    Kaimal, Vivek
    Huang, Xinqiang
    Chang, Aaron N.
    Li, Shenyang
    Kalra, Aarti
    Grafals, Monica
    Portilla, Didier
    MacKenna, Deidre A.
    Orkin, Stuart H.
    Duffield, Jeremy S.
    [J]. SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (121)
  • [3] Critical Role for IL-6 in Hypertrophy and Fibrosis in Chronic Cardiac Allograft Rejection
    Diaz, J. A.
    Booth, A. J.
    Lu, G.
    Wood, S. C.
    Pinsky, D. J.
    Bishop, D. K.
    [J]. AMERICAN JOURNAL OF TRANSPLANTATION, 2009, 9 (08) : 1773 - 1783
  • [4] Duong Van Huyen JP, 2014, EUR HEART J
  • [5] Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease
    Fan, Dong
    Takawale, Abhijit
    Lee, Jiwon
    Kassiri, Zamaneh
    [J]. FIBROGENESIS & TISSUE REPAIR, 2012, 5
  • [6] Gene transfer of RANTES and MCP-1 chemokine antagonists prolongs cardiac allograft survival
    Fleury, S.
    Li, J.
    Simeoni, E.
    Fiorini, E.
    von Segesser, L. K.
    Kappenberger, L.
    Vassalli, G.
    [J]. GENE THERAPY, 2006, 13 (14) : 1104 - 1109
  • [7] Changes in left and right ventricular function of donor hearts during the first year after heart transplantation
    Goland, Sorel
    Siegel, Robert J.
    Burton, Kevin
    De Robertis, Michele A.
    Rafique, Asim
    Schwarz, Ernst
    Zivari, Kaveh
    Mirocha, James
    Trento, Alfredo
    Czer, Lawrence S. C.
    [J]. HEART, 2011, 97 (20) : 1681 - 1686
  • [8] Heterotopic vascularized murine cardiac transplantation to study graft arteriopathy
    Hasegawa, Tomomi
    Visovatti, Scott H.
    Hyman, Matthew C.
    Hayasaki, Takanori
    Pinsky, David J.
    [J]. NATURE PROTOCOLS, 2007, 2 (03) : 471 - 480
  • [9] Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy
    Haudek, Sandra B.
    Cheng, Jizhong
    Du, Jie
    Wang, Yanlin
    Hermosillo-Rodriguez, Jesus
    Trial, JoAnn
    Taffet, George E.
    Entman, Mark L.
    [J]. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2010, 49 (03) : 499 - 507
  • [10] Treatment of HCV Infection by Targeting MicroRNA
    Janssen, Harry L. A.
    Reesink, Hendrik W.
    Lawitz, Eric J.
    Zeuzem, Stefan
    Rodriguez-Torres, Maribel
    Patel, Keyur
    van der Meer, Adriaan J.
    Patick, Amy K.
    Chen, Alice
    Zhou, Yi
    Persson, Robert
    King, Barney D.
    Kauppinen, Sakari
    Levin, Arthur A.
    Hodges, Michael R.
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2013, 368 (18) : 1685 - 1694