Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure*

被引:16
作者
Bosch, Lena [1 ]
de Haan, Judith [1 ]
Seijkens, Tom [2 ,3 ]
van Tiel, Claudia [2 ]
Brans, Maike [1 ]
Pasterkamp, Gerard [4 ]
Lutgens, Esther [2 ,3 ]
de Jager, Saskia [1 ,5 ]
机构
[1] Univ Med Ctr Utrecht, Expt Cardiol, Utrecht, Netherlands
[2] Acad Med Ctr Amsterdam, Dept Med Biochem, Amsterdam, Netherlands
[3] Ludwig Maximilians Univ Munchen, Inst Cardiovasc Prevent IPEK, Munich, Germany
[4] Univ Utrecht, Univ Med Ctr Utrecht, Dept Clin Chem & Haematol, Ctr Circulatory Hlth, Utrecht, Netherlands
[5] Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands
基金
欧盟地平线“2020”;
关键词
Inflammation; Heart failure; Basic science research; Animal models cardiovascular disease;
D O I
10.1016/j.ijcard.2018.12.076
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: CD40 signalling is involved in chronic inflammation, a condition that plays an important role in nonischemic heart failure (HF). Small molecule inhibitors of CD4O-TRAF6 have shown to be effective in multiple animal models of chronic inflammatory disease, such as obesity and atherosclerosis. Methods &results: Mice were subjected lo transverse aortic constriction (TAC) and randomized to small molecule inhibition of CD4O-TRAF6 or placebo. CD40-TRAF6 inhibition resulted in less cardiac remodelling 10 weeks atter TAC with a reduced end systolic volume (TAC-placebo group: 71.9 +/- 8.8 vs TAC-CD4O-TRAF6 inhibitor: 53.7 +/- 6.1 IA, p 0.03) and improved ejection fraction (EF) compared to placebo (TAC-placebo group: 25.6 +/- 2.8 vs TAC-CD4O-TRAF6 inhibitor: 35.5 3.3%, p 0.02). Within the myocardium, CD4O-TRAF6 inhibition resulted in decreased macrophage and T-cell infiltration 10 weeks after TAC compared to placebo. In addition, a decrease in fibrosis and cardioniyocyte hypertrophy was observed in the CD4O-TRAF6 inhibitor group compared to placebo. Conclusion: CD4O-TRAF6 inhibition improves cardiac function in non-ischemic HE in mice. This effect is mediated by a reduction in macrophage and T-cell influx in the myocardium accompanied by a reduction in cardiac fibrosis and hypertrophy. (C) 2019 The Authors. Published by Elsevier B.V.
引用
收藏
页码:141 / 144
页数:4
相关论文
共 13 条
  • [1] Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance
    Chatzigeorgioua, Antonios
    Seijkens, Tom
    Zarzycka, Barbara
    Engel, David
    Poggi, Marjorie
    van den Berg, Susan
    van den Berg, Sjoerd
    Soehnlein, Oliver
    Winkels, Holger
    Beckers, Linda
    Lievens, Dirk
    Driessen, Ann
    Kusters, Pascal
    Biessen, Erik
    Garcia-Martin, Ruben
    Ameln, Anne Klotzsche-von
    Gijbels, Marion
    Noelle, Randolph
    Boon, Louis
    Hackeng, Tilman
    Schulte, Klaus
    Xu, Aimin
    Vriend, Gert
    Nabuurs, Sander
    Chung, Kyoung-Jin
    van Dijk, Ko Willems
    Rensen, Patrick C. N.
    Gerdes, Norbert
    de Winther, Menno
    Block, Norman L.
    Schally, Andrew V.
    Weber, Christian
    Bornstein, Stefan R.
    Nicolaes, Gerry
    Chavakis, Triantafyllos
    Lutgens, Esther
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (07) : 2686 - 2691
  • [2] Complement 5a Receptor deficiency does not influence adverse cardiac remodeling after pressure-overload in mice
    de Haan, Judith J.
    Bosch, Lena
    Borgman, Anouska
    Bastemeijer, Marissa
    Brans, Maike A. D.
    de Weg, Sander M. van
    de Kleijn, Dominique P. V.
    Sluijter, Joost P. G.
    el Azzouzi, Hamid
    de Jager, Saskia C. A.
    [J]. SCIENTIFIC REPORTS, 2017, 7
  • [3] Chronic Heart Failure and Inflammation What Do We Really Know?
    Dick, Sarah A.
    Epelman, Slava
    [J]. CIRCULATION RESEARCH, 2016, 119 (01) : 159 - 176
  • [4] Molecular mechanism and function of CD40/CD40L engagement in the immune system
    Elgueta, Raul
    Benson, Micah J.
    de Vries, Victor C.
    Wasiuk, Anna
    Guo, Yanxia
    Noelle, Randolph J.
    [J]. IMMUNOLOGICAL REVIEWS, 2009, 229 : 152 - 172
  • [5] CD40L contributes to angiotensin II-induced pro-thrombotic state, vascular inflammation, oxidative stress and endothelial dysfunction
    Hausding, Michael
    Jurk, Kerstin
    Daub, Steffen
    Kroeller-Schoen, Swenja
    Stein, Judith
    Schwenk, Melanie
    Oelze, Matthias
    Mikhed, Yuliya
    Kerahrodi, Jasmin Ghaemi
    Kossmann, Sabine
    Jansen, Thomas
    Schulz, Eberhard
    Wenzel, Philip
    Reske-Kunz, Angelika B.
    Becker, Christian
    Muenzel, Thomas
    Grabbe, Stephan
    Daiber, Andreas
    [J]. BASIC RESEARCH IN CARDIOLOGY, 2013, 108 (06)
  • [6] How can we cure a heart "in flame"? A translational view on inflammation in heart failure
    Hofmann, Ulrich
    Frantz, Stefan
    [J]. BASIC RESEARCH IN CARDIOLOGY, 2013, 108 (04)
  • [7] T cell costimulation blockade blunts pressure overload-induced heart failure
    Kallikourdis, Marinos
    Martini, Elisa
    Carullo, Pierluigi
    Sardi, Claudia
    Roselli, Giuliana
    Greco, Carolina M.
    Vignali, Debora
    Riva, Federica
    Berre, Anne Marie Ormbostad
    Stolen, Tomas O.
    Fumero, Andrea
    Faggian, Giuseppe
    Di Pasquale, Elisa
    Elia, Leonardo
    Rumio, Cristiano
    Catalucci, Daniele
    Papait, Roberto
    Condorelli, Gianluigi
    [J]. NATURE COMMUNICATIONS, 2017, 8
  • [8] Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile
    Lutgens, Esther
    Lievens, Dirk
    Beckers, Linda
    Wijnands, Erwin
    Soehnlein, Oliver
    Zernecke, Alma
    Seijkens, Tom
    Engel, David
    Cleutjens, Jack
    Keller, Anna M.
    Naik, Shalin H.
    Boon, Louis
    Oufella, Hafid Ait
    Mallat, Ziad
    Ahonen, Cory L.
    Noelle, Randolph J.
    de Winther, Menno P.
    Daemen, Mat J.
    Biessen, Erik A.
    Weber, Christian
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2010, 207 (02) : 391 - 404
  • [9] Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure
    Nevers, Tania
    Salvador, Ane M.
    Velazquez, Francisco
    Ngwenyama, Njabulo
    Carrillo-Salinas, Francisco J.
    Aronovitz, Mark
    Blanton, Robert M.
    Alcaide, Pilar
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2017, 214 (11) : 3311 - 3329
  • [10] Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis
    Seijkens, Tom T. P.
    van Tiel, Claudia M.
    Kusters, Pascal J. H.
    Atzler, Dorothee
    Soehnlein, Oliver
    Zarzycka, Barbara
    Aarts, Suzanne A. B. M.
    Lameijer, Marnix
    Gijbels, Marion J.
    Beckers, Linda
    den Toom, Myrthe
    Slutter, Bram
    Kuiper, Johan
    Duchene, Johan
    Aslani, Maria
    Megens, Remco T. A.
    van 't Veer, Cornelis
    Kooij, Gijs
    Schrijver, Roy
    Hoeksema, Marten A.
    Boon, Louis
    Fay, Francois
    Tang, Jun
    Baxter, Samantha
    Jongejan, Aldo
    Moerland, Perry D.
    Vriend, Gert
    Bleijlevens, Boris
    Fisher, Edward A.
    Duivenvoorden, Raphael
    Gerdes, Norbert
    de Winther, Menno P. J.
    Nicolaes, Gerry A.
    Mulder, Willem J. M.
    Weber, Christian
    Lutgens, Esther
    [J]. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2018, 71 (05) : 527 - 542