Top

Published in:

Open Access 01-07-2017 | Original Contribution

Splenic Ly6C^hi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice

Authors: Mateusz Tomczyk, Izabela Kraszewska, Krzysztof Szade, Karolina Bukowska-Strakova, Marco Meloni, Alicja Jozkowicz, Jozef Dulak, Agnieszka Jazwa

Published in: Basic Research in Cardiology | Issue 4/2017

Abstract

Heme oxygenase-1 (Hmox1) is a stress-inducible protein crucial in heme catabolism. The end products of its enzymatic activity possess anti-oxidative, anti-apoptotic and anti-inflammatory properties. Cardioprotective effects of Hmox1 were demonstrated in experimental models of myocardial infarction (MI). Nevertheless, its importance in timely resolution of post-ischemic inflammation remains incompletely understood. The aim of this study was to determine the role of Hmox1 in the monocyte/macrophage-mediated cardiac remodeling in a mouse model of MI. Hmox1 knockout (Hmox1^−/−) and wild-type (WT, Hmox1^+/+) mice were subjected to a permanent ligation of the left anterior descending coronary artery. Significantly lower incidence of left ventricle (LV) free wall rupture was noted between 3rd and 5th day after MI in Hmox1^−/− mice resulting in their better overall survival. Then, starting from 7th until 21st day post-MI a more potent deterioration of LV function was observed in Hmox1^−/− than in the surviving Hmox1^+/+ mice. This was accompanied by higher numbers of Ly6C^hi monocytes in peripheral blood, as well as higher expression of monocyte chemoattractant protein-1 and adhesion molecules in the hearts of MI-operated Hmox1^−/− mice. Consequently, a greater post-MI monocyte-derived myocardial macrophage infiltration was noted in Hmox1-deficient individuals. Splenectomy decreased the numbers of circulating inflammatory Ly6C^hi monocytes in blood, reduced the numbers of proinflammatory cardiac macrophages and significantly improved the post-MI LV function in Hmox1^−/− mice. In conclusion, Hmox1 deficiency has divergent consequences in MI. On the one hand, it improves early post-MI survival by decreasing the occurrence of cardiac rupture. Afterwards, however, the hearts of Hmox1-deficient mice undergo adverse late LV remodeling due to overactive and prolonged post-ischemic inflammatory response. We identified spleen as an important source of these cardiovascular complications in Hmox1^−/− mice.

Available only for authorised users

Ahn D, Cheng L, Moon C, Spurgeon H, Lakatta EG, Talan MI (2004) Induction of myocardial infarcts of a predictable size and location by branch pattern probability-assisted coronary ligation in C57BL/6 mice. Am J Physiol Heart Circ Physiol 286:H1201–H1207. doi:10.1152/ajpheart.00862.2003 CrossRefPubMed

Bohl S, Medway DJ, Schulz-Menger J, Schneider JE, Neubauer S, Lygate CA (2009) Refined approach for quantification of in vivo ischemia–reperfusion injury in the mouse heart. Am J Physiol Heart Circ Physiol 297:H2054–H2058. doi:10.1152/ajpheart.00836.2009 CrossRefPubMedPubMedCentral

Butcher EC, Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272:60–66. doi:10.1126/science.272.5258.60 CrossRefPubMed

Cao YA, Wagers AJ, Karsunky H, Zhao H, Reeves R, Wong RJ, Stevenson DK, Weissman IL, Contag CH (2008) Heme oxygenase-1 deficiency leads to disrupted response to acute stress in stem cells and progenitors. Blood 112:4494–4502. doi:10.1182/blood-2007-12-127621 CrossRefPubMedPubMedCentral

Charney RH, Takahashi S, Zhao M, Sonnenblick EH, Eng C (1992) Collagen loss in the stunned myocardium. Circulation 85:1483–1490. doi:10.1161/01.CIR.85.4.1483 CrossRefPubMed

Cheng C, Noordeloos AM, Jeney V, Soares MP, Moll F, Pasterkamp G, Serruys PW, Duckers HJ (2009) Heme oxygenase 1 determines atherosclerotic lesion progression into a vulnerable plaque. Circulation 119:3017–3027. doi:10.1161/CIRCULATIONAHA.108.808618 CrossRefPubMed

Czibik G, Derumeaux G, Sawaki D, Valen G, Motterlini R (2014) Heme oxygenase-1: an emerging therapeutic target to curb cardiac pathology. Basic Res Cardiol 109:450. doi:10.1007/s00395-014-0450-9 CrossRefPubMed

Daenen KE, Martens P, Bammens B (2015) Association of HO-1 (GT)n promoter polymorphism and cardiovascular disease: a reanalysis of the literature. Can J Cardiol 32:160–168. doi:10.1016/j.cjca.2015.06.006 CrossRefPubMed

Deshane J, Chen S, Caballero S, Grochot-Przeczek A, Was H, Li Calzi S, Lach R, Hock TD, Chen B, Hill-Kapturczak N, Siegal GP, Dulak J, Jozkowicz A, Grant MB, Agarwal A (2007) Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism. J Exp Med 204:605–618. doi:10.1084/jem.20061609 CrossRefPubMedPubMedCentral

10.

Dewald O, Zymek P, Winkelmann K, Koerting A, Ren G, Abou-Khamis T, Michael LH, Rollins BJ, Entman ML, Frangogiannis NG (2005) CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res 96:881–889. doi:10.1161/01.RES.0000163017.13772.3a CrossRefPubMed

11.

Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HW, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M (2012) Myocardial infarction accelerates atherosclerosis. Nature 487:325–329. doi:10.1038/nature11260 CrossRefPubMedPubMedCentral

12.

Dutta P, Sager HB, Stengel KR, Naxerova K, Courties G, Saez B, Silberstein L, Heidt T, Sebas M, Sun Y, Wojtkiewicz G, Feruglio PF, King K, Baker JN, van der Laan AM, Borodovsky A, Fitzgerald K, Hulsmans M, Hoyer F, Iwamoto Y, Vinegoni C, Brown D, Di Carli M, Libby P, Hiebert SW, Scadden DT, Swirski FK, Weissleder R, Nahrendorf M (2015) Myocardial infarction activates CCR2(+) hematopoietic stem and progenitor cells. Cell Stem Cell 16:477–487. doi:10.1016/j.stem.2015.04.008 CrossRefPubMedPubMedCentral

13.

Engstrom G, Melander O, Hedblad B (2009) Leukocyte count and incidence of hospitalizations due to heart failure. Circ Heart Fail 2:217–222. doi:10.1161/CIRCHEARTFAILURE.108.827071 CrossRefPubMed

14.

Epelman S, Lavine KJ, Beaudin AE, Sojka DK, Carrero JA, Calderon B, Brija T, Gautier EL, Ivanov S, Satpathy AT, Schilling JD, Schwendener R, Sergin I, Razani B, Forsberg EC, Yokoyama WM, Unanue ER, Colonna M, Randolph GJ, Mann DL (2014) Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40:91–104. doi:10.1016/j.immuni.2013.11.019 CrossRefPubMedPubMedCentral

15.

Epelman S, Lavine KJ, Randolph GJ (2014) Origin and functions of tissue macrophages. Immunity 41:21–35. doi:10.1016/j.immuni.2014.06.013 CrossRefPubMedPubMedCentral

16.

Epelman S, Liu PP, Mann DL (2015) Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat Rev Immunol 15:117–129. doi:10.1038/nri3800 CrossRefPubMedPubMedCentral

17.

Figueras J, Alcalde O, Barrabes JA, Serra V, Alguersuari J, Cortadellas J, Lidon RM (2008) Changes in hospital mortality rates in 425 patients with acute ST-elevation myocardial infarction and cardiac rupture over a 30-year period. Circulation 118:2783–2789. doi:10.1161/CIRCULATIONAHA.108.776690 CrossRefPubMed

18.

Gao XM, Dilley RJ, Samuel CS, Percy E, Fullerton MJ, Dart AM, Du XJ (2002) Lower risk of postinfarct rupture in mouse heart overexpressing beta 2-adrenergic receptors: importance of collagen content. J Cardiovasc Pharmacol 40:632–640. doi:10.1097/01.FJC.0000026003.28302.C1 CrossRefPubMed

19.

Gao XM, Xu Q, Kiriazis H, Dart AM, Du XJ (2005) Mouse model of post-infarct ventricular rupture: time course, strain- and gender-dependency, tensile strength, and histopathology. Cardiovasc Res 65:469–477. doi:10.1016/j.cardiores.2004.10.014 CrossRefPubMed

20.

Grochot-Przeczek A, Lach R, Mis J, Skrzypek K, Gozdecka M, Sroczynska P, Dubiel M, Rutkowski A, Kozakowska M, Zagorska A, Walczynski J, Was H, Kotlinowski J, Drukala J, Kurowski K, Kieda C, Herault Y, Dulak J, Jozkowicz A (2009) Heme oxygenase-1 accelerates cutaneous wound healing in mice. PLoS One 4:e5803. doi:10.1371/journal.pone.0005803 CrossRefPubMedPubMedCentral

21.

Heusch G, Libby P, Gersh B, Yellon D, Bohm M, Lopaschuk G, Opie L (2014) Cardiovascular remodelling in coronary artery disease and heart failure. Lancet 383:1933–1943. doi:10.1016/S0140-6736(14)60107-0 CrossRefPubMedPubMedCentral

22.

Hinkel R, Lange P, Petersen B, Gottlieb E, Ng JK, Finger S, Horstkotte J, Lee S, Thormann M, Knorr M, El-Aouni C, Boekstegers P, Reichart B, Wenzel P, Niemann H, Kupatt C (2015) Heme oxygenase-1 gene therapy provides cardioprotection via control of post-ischemic inflammation: an experimental study in a pre-clinical pig model. J Am Coll Cardiol 66:154–165. doi:10.1016/j.jacc.2015.04.064 CrossRefPubMed

23.

Hume DA (2008) Macrophages as APC and the dendritic cell myth. J Immunol 181:5829–5835. doi:10.4049/jimmunol.181.9.5829 CrossRefPubMed

24.

Jazwa A, Florczyk U, Grochot-Przeczek A, Krist B, Loboda A, Jozkowicz A, Dulak J (2016) Limb ischemia and vessel regeneration: is there a role for VEGF? Vasc Pharmacol 86:18–30. doi:10.1016/j.vph.2016.09.003 CrossRef

25.

Jazwa A, Stepniewski J, Zamykal M, Jagodzinska J, Meloni M, Emanueli C, Jozkowicz A, Dulak J (2013) Pre-emptive hypoxia-regulated HO-1 gene therapy improves post-ischaemic limb perfusion and tissue regeneration in mice. Cardiovasc Res 97:115–124. doi:10.1093/cvr/cvs284 CrossRefPubMed

26.

Jazwa A, Stoszko M, Tomczyk M, Bukowska-Strakova K, Pichon C, Jozkowicz A, Dulak J (2015) HIF-regulated HO-1 gene transfer improves the post-ischemic limb recovery and diminishes TLR-triggered immune responses—effects modified by concomitant VEGF overexpression. Vasc Pharmacol 71:127–138. doi:10.1016/j.vph.2015.02.011 CrossRef

27.

Kozakowska M, Szade K, Dulak J, Jozkowicz A (2014) Role of heme oxygenase-1 in postnatal differentiation of stem cells: a possible cross-talk with microRNAs. Antioxid Redox Signal 20:1827–1850. doi:10.1089/ars.2013.5341 CrossRefPubMedPubMedCentral

28.

Lakkisto P, Siren JM, Kyto V, Forsten H, Laine M, Pulkki K, Tikkanen I (2011) Heme oxygenase-1 induction protects the heart and modulates cellular and extracellular remodelling after myocardial infarction in rats. Exp Biol Med (Maywood) 236:1437–1448. doi:10.1258/ebm.2011.011148 CrossRef

29.

Lavine KJ, Epelman S, Uchida K, Weber KJ, Nichols CG, Schilling JD, Ornitz DM, Randolph GJ, Mann DL (2014) Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc Natl Acad Sci USA 111:16029–16034. doi:10.1073/pnas.1406508111 CrossRefPubMedPubMedCentral

30.

Li Volti G, Wang J, Traganos F, Kappas A, Abraham NG (2002) Differential effect of heme oxygenase-1 in endothelial and smooth muscle cell cycle progression. Biochem Biophys Res Commun 296:1077–1082. doi:10.1016/S0006-291X(02)02054-5 CrossRefPubMed

31.

Lin Q, Weis S, Yang G, Weng YH, Helston R, Rish K, Smith A, Bordner J, Polte T, Gaunitz F, Dennery PA (2007) Heme oxygenase-1 protein localizes to the nucleus and activates transcription factors important in oxidative stress. J Biol Chem 282:20621–20633. doi:10.1074/jbc.M607954200 CrossRefPubMed

32.

Liu X, Pachori AS, Ward CA, Davis JP, Gnecchi M, Kong D, Zhang L, Murduck J, Yet SF, Perrella MA, Pratt RE, Dzau VJ, Melo LG (2006) Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function. FASEB J 20:207–216. doi:10.1096/fj.05-4435com CrossRefPubMed

33.

Loboda A, Jazwa A, Grochot-Przeczek A, Rutkowski AJ, Cisowski J, Agarwal A, Jozkowicz A, Dulak J (2008) Heme oxygenase-1 and the vascular bed: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 10:1767–1812. doi:10.1089/ars.2008.2043 CrossRefPubMed

34.

Maines MD (1988) Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J 2:2557–2568PubMed

35.

Majmudar MD, Keliher EJ, Heidt T, Leuschner F, Truelove J, Sena BF, Gorbatov R, Iwamoto Y, Dutta P, Wojtkiewicz G, Courties G, Sebas M, Borodovsky A, Fitzgerald K, Nolte MW, Dickneite G, Chen JW, Anderson DG, Swirski FK, Weissleder R, Nahrendorf M (2013) Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice. Circulation 127:2038–2046. doi:10.1161/CIRCULATIONAHA.112.000116 CrossRefPubMedPubMedCentral

36.

Meloni M, Caporali A, Graiani G, Lagrasta C, Katare R, Van Linthout S, Spillmann F, Campesi I, Madeddu P, Quaini F, Emanueli C (2010) Nerve growth factor promotes cardiac repair following myocardial infarction. Circ Res 106:1275–1284. doi:10.1161/CIRCRESAHA.109.210088 CrossRefPubMedPubMedCentral

37.

Nahrendorf M, Pittet MJ, Swirski FK (2010) Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation 121:2437–2445. doi:10.1161/CIRCULATIONAHA.109.916346 CrossRefPubMedPubMedCentral

38.

Ndisang JF, Jadhav A (2009) Upregulating the heme oxygenase system suppresses left ventricular hypertrophy in adult spontaneously hypertensive rats for 3 months. J Card Fail 15:616–628. doi:10.1016/j.cardfail.2009.02.003 CrossRefPubMed

39.

Orozco LD, Kapturczak MH, Barajas B, Wang X, Weinstein MM, Wong J, Deshane J, Bolisetty S, Shaposhnik Z, Shih DM, Agarwal A, Lusis AJ, Araujo JA (2007) Heme oxygenase-1 expression in macrophages plays a beneficial role in atherosclerosis. Circ Res 100:1703–1711. doi:10.1161/CIRCRESAHA.107.151720 CrossRefPubMed

40.

Robbins CS, Chudnovskiy A, Rauch PJ, Figueiredo JL, Iwamoto Y, Gorbatov R, Etzrodt M, Weber GF, Ueno T, van Rooijen N, Mulligan-Kehoe MJ, Libby P, Nahrendorf M, Pittet MJ, Weissleder R, Swirski FK (2012) Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions. Circulation 125:364–374. doi:10.1161/CIRCULATIONAHA.111.061986 CrossRefPubMed

41.

Sager HB, Hulsmans M, Lavine KJ, Moreira MB, Heidt T, Courties G, Sun Y, Iwamoto Y, Tricot B, Khan OF, Dahlman JE, Borodovsky A, Fitzgerald K, Anderson DG, Weissleder R, Libby P, Swirski FK, Nahrendorf M (2016) Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure. Circ Res 119:853–864. doi:10.1161/CIRCRESAHA.116.309001 CrossRefPubMed

42.

Sane DC, Mozingo WS, Becker RC (2009) Cardiac rupture after myocardial infarction: new insights from murine models. Cardiol Rev 17:293–299. doi:10.1097/CRD.0b013e3181bf4ab4 CrossRefPubMed

43.

Strauss-Ayali D, Conrad SM, Mosser DM (2007) Monocyte subpopulations and their differentiation patterns during infection. J Leukoc Biol 82:244–252. doi:10.1189/jlb.0307191 CrossRefPubMed

44.

Swirski FK, Hilgendorf I, Robbins CS (2014) From proliferation to proliferation: monocyte lineage comes full circle. Semin Immunopathol 36:137–148. doi:10.1007/s00281-013-0409-1 CrossRefPubMedPubMedCentral

45.

Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325:612–616. doi:10.1126/science.1175202 CrossRefPubMedPubMedCentral

46.

Varghese AJ (1983) Glutathione conjugates of misonidazole. Biochem Biophys Res Commun 112:1013–1020. doi:10.1016/0006-291X(83)91719-9 CrossRefPubMed

47.

Wang G, Hamid T, Keith RJ, Zhou G, Partridge CR, Xiang X, Kingery JR, Lewis RK, Li Q, Rokosh DG, Ford R, Spinale FG, Riggs DW, Srivastava S, Bhatnagar A, Bolli R, Prabhu SD (2010) Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart. Circulation 121:1912–1925. doi:10.1161/CIRCULATIONAHA.109.905471 CrossRefPubMedPubMedCentral

48.

Wegiel B, Chin BY, Otterbein LE (2008) Inhale to survive, cycle or die? Carbon monoxide and cellular proliferation. Cell Cycle 7:1379–1384. doi:10.4161/cc.7.10.5948 CrossRefPubMed

49.

Wegiel B, Hedblom A, Li M, Gallo D, Csizmadia E, Harris C, Nemeth Z, Zuckerbraun BS, Soares M, Persson JL, Otterbein LE (2014) Heme oxygenase-1 derived carbon monoxide permits maturation of myeloid cells. Cell Death Dis 5:e1139. doi:10.1038/cddis.2014.97 CrossRefPubMedPubMedCentral

50.

Whittaker P, Boughner DR, Kloner RA (1991) Role of collagen in acute myocardial infarct expansion. Circulation 84:2123–2134. doi:10.1161/01.CIR.84.5.2123 CrossRefPubMed

51.

Wilson A, Trumpp A (2006) Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6:93–106. doi:10.1038/nri1779 CrossRefPubMed

52.

Yeh YH, Hsu LA, Chen YH, Kuo CT, Chang GJ, Chen WJ (2016) Protective role of heme oxygenase-1 in atrial remodeling. Basic Res Cardiol 111:58. doi:10.1007/s00395-016-0577-y CrossRefPubMed

53.

Yet SF, Layne MD, Liu X, Chen YH, Ith B, Sibinga NE, Perrella MA (2003) Absence of heme oxygenase-1 exacerbates atherosclerotic lesion formation and vascular remodeling. FASEB J 17:1759–1761. doi:10.1096/fj.03-0187fje PubMed

54.

Yet SF, Tian R, Layne MD, Wang ZY, Maemura K, Solovyeva M, Ith B, Melo LG, Zhang L, Ingwall JS, Dzau VJ, Lee ME, Perrella MA (2001) Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res 89:168–173. doi:10.1161/hh1401.093314 CrossRefPubMed

55.

Yoshida T, Maulik N, Ho YS, Alam J, Das DK (2001) H(mox-1) constitutes an adaptive response to effect antioxidant cardioprotection: a study with transgenic mice heterozygous for targeted disruption of the Heme oxygenase-1 gene. Circulation 103:1695–1701. doi:10.1161/01.CIR.103.12.1695 CrossRefPubMed

56.

Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, Leenen PJ, Liu YJ, MacPherson G, Randolph GJ, Scherberich J, Schmitz J, Shortman K, Sozzani S, Strobl H, Zembala M, Austyn JM, Lutz MB (2010) Nomenclature of monocytes and dendritic cells in blood. Blood 116:e74–e80. doi:10.1182/blood-2010-02-258558 CrossRefPubMed

Title: Splenic Ly6Chi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice
Authors: Mateusz Tomczyk
Izabela Kraszewska
Krzysztof Szade
Karolina Bukowska-Strakova
Marco Meloni
Alicja Jozkowicz
Jozef Dulak
Agnieszka Jazwa
Publication date: 01-07-2017
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 4/2017
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-017-0629-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Splenic Ly6C^hi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2017

Erratum to: Changes of myocardial gene expression and protein composition in patients with dilated cardiomyopathy after immunoadsorption with subsequent immunoglobulin substitution

Expression and regulation of type 2A protein phosphatases and alpha4 signalling in cardiac health and hypertrophy

Fast therapeutic hypothermia prevents post-cardiac arrest syndrome through cyclophilin D-mediated mitochondrial permeability transition inhibition

Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation

Dissecting the role of myeloid and mesenchymal fibroblasts in age-dependent cardiac fibrosis

The crucial role of activin A/ALK4 pathway in the pathogenesis of Ang-II-induced atrial fibrosis and vulnerability to atrial fibrillation