nach oben

Heart and Vessels

Erschienen in:

01.07.2015 | Original Article

A P2X7 receptor antagonist attenuates experimental autoimmune myocarditis via suppressed myocardial CD4⁺ T and macrophage infiltration and NADPH oxidase 2/4 expression in mice

verfasst von: Hirofumi Zempo, Yoichiro Sugita, Masahito Ogawa, Ryo Watanabe, Jun-ichi Suzuki, Mitsuaki Isobe

Erschienen in: Heart and Vessels | Ausgabe 4/2015

Einloggen, um Zugang zu erhalten

Abstract

Myocarditis is a clinically serious disease; however, no effective treatment has been elucidated. The P2X7 receptor is related to the pathophysiology of inflammation in many cardiovascular diseases. The P2X7 receptor antagonist is promising as an immunosuppressive treatment; however, its role in myocarditis is still to be established. To clarify the role of the P2X7 receptor, we used a murine experimental autoimmune myocarditis (EAM) model. Mice were immunized on day 0 and 7 with synthetic cardiac myosin peptide to establish EAM. The mice with induced EAM were treated with A740003, the P2X7 receptor antagonist (n = 10), or not treated (n = 11); hearts were harvested on day 21. The P2X7 receptor antagonist improved myocardial contraction of the EAM hearts via suppressed infiltration of CD4⁺ T cells and macrophages. Similarly, mRNA expression of interleukin 1 beta, the P2X7 receptor and NADPH oxidase 2/4 was lower in the heart of the P2X7 receptor antagonist-treated group compared to the non-treat group. The P2X7 receptor antagonist suppressed EAM development; thus, this inhibition is promising for treating clinical myocarditis.

Andreka P, Nadhazi Z, Muzes G, Szantho G, Vandor L, Konya L, Turner MS, Tulassay Z, Bishopric NH (2004) Possible therapeutic targets in cardiac myocyte apoptosis. Curr Pharm Des 10:2445–2461PubMedCrossRef

Suzuki J, Ogawa M, Futamatsu H, Kosuge H, Sagesaka YM, Isobe M (2007) Tea catechins improve left ventricular dysfunction, suppress myocardial inflammation and fibrosis, and alter cytokine expression in rat autoimmune myocarditis. Eur J Heart Fail 9:152–159PubMedCrossRef

Ashigaki N, Suzuki J, Ogawa M, Watanabe R, Aoyama N, Kobayashi N, Hanatani T, Sekinishi A, Zempo H, Tada Y, Takamura C, Wakayama K, Hirata Y, Nagai R, Izumi Y, Isobe M (2013) Periodontal bacteria aggravate experimental autoimmune myocarditis in mice. Am J Physiol Heart Circ Physiol 304:H740–H748PubMedCrossRef

Sagar S, Liu PP, Cooper LT (2012) Myocarditis. Lancet 379:738–747PubMedCrossRef

Kawai C (1999) From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future. Circulation 99:1091–1100PubMedCrossRef

Caforio AL, Marcolongo R, Jahns R, Fu M, Felix SB, Iliceto S (2012) Immune-mediated and autoimmune myocarditis: clinical presentation, diagnosis and management. Heart Fail Rev 18:715–732CrossRef

Lv H, Havari E, Pinto S, Gottumukkala RV, Cornivelli L, Raddassi K, Matsui T, Rosenzweig A, Bronson RT, Smith R, Fletcher AL, Turley SJ, Wucherpfennig K, Kyewski B, Lipes MA (2011) Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans. J Clin Invest 121:1561–1573PubMedCentralPubMedCrossRef

Marchant DJ, Boyd JH, Lin DC, Granville DJ, Garmaroudi FS, McManus BM (2012) Inflammation in myocardial diseases. Circ Res 110:126–144PubMedCrossRef

Kishimoto C, Shioji K, Hashimoto T, Nonogi H, Lee JD, Kato S, Hiramitsu S, Morimoto SI (2013) Therapy with immunoglobulin in patients with acute myocarditis and cardiomyopathy: analysis of leukocyte balance. Heart Vessels. doi:10.1007/s00380-013-0368-4

10.

Yuan J, Cao AL, Yu M, Lin QW, Yu X, Zhang JH, Wang M, Guo HP, Liao YH (2010) Th17 cells facilitate the humoral immune response in patients with acute viral myocarditis. J Clin Immunol 30:226–234PubMedCrossRef

11.

Suzuki J, Ogawa M, Watanabe R, Morishita R, Hirata Y, Nagai R, Isobe M (2011) Autoimmune giant cell myocarditis: clinical characteristics, experimental models and future treatments. Expert Opin Ther Targets 15:1163–1172PubMedCrossRef

12.

Wiley JS, Sluyter R, Gu BJ, Stokes L, Fuller SJ (2011) The human P2X7 receptor and its role in innate immunity. Tissue Antigens 78:321–332PubMedCrossRef

13.

Rathinam VA, Vanaja SK, Fitzgerald KA (2012) Regulation of inflammasome signaling. Nat Immunol 13:333–342PubMedCentralPubMedCrossRef

14.

Matute C, Torre I, Pérez-Cerdá F, Pérez-Samartín A, Alberdi E, Etxebarria E, Arranz AM, Ravid R, Rodríguez-Antigüedad A, Sánchez-Gómez M, Domercq M (2007) P2X(7) receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J Neurosci 27:9525–9533PubMedCrossRef

15.

Kurashima Y, Amiya T, Nochi T, Fujisawa K, Haraguchi T, Iba H, Tsutsui H, Sato S, Nakajima S, Iijima H, Kubo M, Kunisawa J, Kiyono H (2012) Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors. Nat Commun 3:1034PubMedCentralPubMedCrossRef

16.

Vergani A, Tezza S, D’Addio F, Fotino C, Liu K, Niewczas M, Bassi R, Molano RD, Kleffel S, Petrelli A, Soleti A, Ammirati E, Frigerio M, Visner G, Grassi F, Ferrero ME, Corradi D, Abdi R, Ricordi C, Sayegh MH, Pileggi A, Fiorina P (2013) Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. Circulation 127:463–475PubMedCentralPubMedCrossRef

17.

Pummerer CL, Luze K, Grässl G, Bachmaier K, Offner F, Burrell SK, Lenz DM, Zamborelli TJ, Penninger JM, Neu N (1996) Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice. J Clin Invest 97:2057–2062PubMedCentralPubMedCrossRef

18.

Honore P, Donnelly-Roberts D, Namovic MT, Hsieh G, Zhu CZ, Mikusa JP, Hernandez G, Zhong C, Gauvin DM, Chandran P, Harris R, Medrano AP, Carroll W, Marsh K, Sullivan JP, Faltynek CR, Jarvis MF (2006) A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. J Pharmacol Exp Ther 319:1376–1385PubMedCrossRef

19.

Seko Y, Takahashi N, Azuma M, Yagita H, Okumura K, Yazaki Y (1998) Effects of in vivo administration of anti-B7-1/B7-2 monoclonal antibodies on murine acute myocarditis caused by coxsackievirus B3. Circ Res 82:613–618PubMedCrossRef

20.

Shimoyama M, Hayashi D, Zou Y, Takimoto E, Mizukami M, Monzen K, Kudoh S, Hiroi Y, Yazaki Y, Nagai R, Komuro I (2000) Calcineurin inhibitor attenuates the development and induces the regression of cardiac hypertrophy in rats with salt-sensitive hypertension. Circulation 102:1996–2004PubMedCrossRef

21.

Futamatsu H, Suzuki J, Mizuno S, Koga N, Adachi S, Kosuge H, Maejima Y, Hirao K, Nakamura T, Isobe M (2005) Hepatocyte growth factor ameliorates the progression of experimental autoimmune myocarditis: a potential role for induction of T helper 2 cytokines. Circ Res 96:823–830PubMedCrossRef

22.

Volonte C, Apolloni S, Skaper SD, Burnstock G (2012) P2X7 receptors: channels, pores and more. CNS Neurol Disord Drug Targets 11:705–721CrossRef

23.

Lassegue B, San Martin A, Griendling KK (2012) Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res 110:1364–1390PubMedCentralPubMedCrossRef

24.

Han LN, Li TL, Zhang YJ, Yang TS, Ding Y (2011) Experimental study of MMP-2 inhibitor treatment of experimental autoimmune myocarditis in Lewis rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi 27:452–456PubMed

25.

Han LN, Li TL, Zhang YJ, Yang TS, Ding Y, Zhao XN, Guo SL (2011) Effects of matrix metalloproteinase-9 inhibitor in Lewis rats with experimental autoimmune myocarditis. Zhonghua Xin Xue Guan Bing Za Zhi 39:118–123PubMed

26.

Kania G, Blyszczuk P, Eriksson U (2009) Mechanisms of cardiac fibrosis in inflammatory heart disease. Trends Cardiovasc Med 19:247–252PubMedCrossRef

27.

Nabeta T, Inomata T, Iida Y, Ikeda Y, Iwamoto M, Ishii S, Sato T, Watanabe I, Naruke T, Shinagawa H, Koitabashi T, Takeuchi I, Nishii M, Inoue Y, Izumi T (2013) Baseline cardiac magnetic resonance imaging versus baseline endomyocardial biopsy for the prediction of left ventricular reverse remodeling and prognosis in response to therapy in patients with idiopathic dilated cardiomyopathy. Heart Vessels. doi:10.1007/s00380-013-0415-1 PubMedCentral

28.

Smith SC, Allen PM (1991) Myosin-induced acute myocarditis is a T cell-mediated disease. J Immunol 147:2141–2147PubMed

29.

Maier R, Miller S, Kurrer M, Krebs P, de Giuli R, Kremer M, Scandella E, Ludewig B (2005) Quantification and characterization of myosin peptide-specific CD4+ T cells in autoimmune myocarditis. J Immunol Methods 304:117–125PubMedCrossRef

30.

Göser S, Ottl R, Brodner A, Dengler TJ, Torzewski J, Egashira K, Rose NR, Katus HA, Kaya Z (2005) Critical role for monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha in induction of experimental autoimmune myocarditis and effective anti-monocyte chemoattractant protein-1 gene therapy. Circulation 112:3400–3407PubMedCrossRef

31.

Lang PA, Merkler D, Funkner P, Shaabani N, Meryk A, Krings C, Barthuber C, Recher M, Brück W, Häussinger D, Ohashi PS, Lang KS (2010) Oxidized ATP inhibits T-cell-mediated autoimmunity. Eur J Immunol 40:2401–2408PubMedCrossRef

32.

Lemaire I, Falzoni S, Zhang B, Pellegatti P, Di Virgilio F (2011) The P2X7 receptor and Pannexin-1 are both required for the promotion of multinucleated macrophages by the inflammatory cytokine GM-CSF. J Immunol 187:3878–3887PubMedCrossRef

33.

Martel-Gallegos G, Rosales-Saavedra MT, Reyes JP, Casas-Pruneda G, Toro-Castillo C, Pérez-Cornejo P, Arreola J (2010) Human neutrophils do not express purinergic P2X7 receptors. Purinergic Signal 6:297–306PubMedCentralPubMedCrossRef

34.

Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K, Takeda K (2008) ATP drives lamina propria T(H)17 cell differentiation. Nature 455:808–812PubMedCrossRef

35.

Ishiyama S, Hiroe M, Nishikawa T, Shimojo T, Abe S, Fujisaki H, Ito H, Yamakawa K, Kobayashi N, Kasajima T, Marumo F (1998) The Fas/Fas ligand system is involved in the pathogenesis of autoimmune myocarditis in rats. J Immunol 161:4695–4701PubMed

36.

Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E, Buer J, Ricordi C, Westendorf AM, Grassi F (2011) ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci Signal 4:ra12PubMedCrossRef

37.

Killeen ME, Ferris L, Kupetsky EA, Falo L Jr, Mathers AR (2013) Signaling through purinergic receptors for ATP induces human cutaneous innate and adaptive Th17 responses: implications in the pathogenesis of psoriasis. J Immunol 190:4324–4336PubMedCentralPubMedCrossRef

Titel: A P2X7 receptor antagonist attenuates experimental autoimmune myocarditis via suppressed myocardial CD4+ T and macrophage infiltration and NADPH oxidase 2/4 expression in mice
verfasst von: Hirofumi Zempo
Yoichiro Sugita
Masahito Ogawa
Ryo Watanabe
Jun-ichi Suzuki
Mitsuaki Isobe
Publikationsdatum: 01.07.2015
Verlag: Springer Japan
Erschienen in: Heart and Vessels / Ausgabe 4/2015
Print ISSN: 0910-8327
Elektronische ISSN: 1615-2573
DOI: https://doi.org/10.1007/s00380-014-0527-2

Neu im Fachgebiet Kardiologie

24.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

A P2X7 receptor antagonist attenuates experimental autoimmune myocarditis via suppressed myocardial CD4⁺ T and macrophage infiltration and NADPH oxidase 2/4 expression in mice

Abstract

Neu im Fachgebiet Kardiologie

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Wie erfolgreich ist eine Re-Ablation nach Rezidiv?

Europäische Ernährungsgewohnheiten: Das sind die häufigsten Fehler

Parodontalbehandlung verbessert Prognose bei Katheterablation

Update Kardiologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2015

Two cases with past Kawasaki disease developing acute myocardial infarction in their thirties, despite being regarded as at low risk for coronary events

Subacute bioresorbable vascular scaffold thrombosis: a report of 2 cases

Angiographic result of T-stenting with small protrusion using drug-eluting stents in the management of ischemic side branch: the ARTEMIS study

Impact of secondary hyperparathyroidism on ventricular mass regression after aortic valve replacement for aortic stenosis in hemodialysis-dependent patients

Acute changes of left ventricular hemodynamics and function during percutaneous coronary intervention in patients with unprotected left main coronary artery disease

Incidence of periodontitis in Japanese patients with cardiovascular diseases: a comparison between abdominal aortic aneurysm and arrhythmia

Neu im Fachgebiet Kardiologie

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Wie erfolgreich ist eine Re-Ablation nach Rezidiv?

Europäische Ernährungsgewohnheiten: Das sind die häufigsten Fehler

Parodontalbehandlung verbessert Prognose bei Katheterablation

Update Kardiologie