Skip to main content

Advertisement

SpringerLink
Log in

Heme oxygenase-1: an emerging therapeutic target to curb cardiac pathology

  • Review
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Activation of heme oxygenase-1 (HO-1), a heme-degrading enzyme responsive to a wide range of cellular stress, is traditionally considered to convey adaptive responses to oxidative stress, inflammation and vasoconstriction. These diversified effects are achieved through the degradation of heme to carbon monoxide (CO), biliverdin (which is rapidly converted to bilirubin by biliverdin reductase) and ferric iron. Recent findings have added antiproliferative and angiogenic effects to the list of HO-1/CO actions. HO-1 along with its reaction products bilirubin and CO are protective against ischemia-induced injury (myocardial infarction, ischemia—reperfusion (IR)-injury and post-infarct structural remodelling). Moreover, HO-1, and CO in particular, possess acute antihypertensive effects. As opposed to these curative potentials, the long-believed protective effect of HO-1 in cardiac remodelling in response to pressure overload and type 2 diabetes mellitus (DM) has been questioned by recent work. These challenges, coupled with emerging regulatory mechanisms, motivate further in-depth studies to help understand untapped layers of HO-1 regulation and action. The outcomes of these efforts may shed new light on critical mechanisms that could be used to harness the protective potential of this enzyme for the therapeutic benefit of patients suffering from such highly prevalent cardiovascular disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Abid S, Houssaini A, Mouraret N, Marcos E, Amsellem V, Wan F, Dubois-Rande JL, Derumeaux G, Boczkowski J, Motterlini R, Adnot S (2014) P21-dependent protective effects of a carbon monoxide-releasing molecule-3 in pulmonary hypertension. Arterioscler Thromb Vasc Biol 34:304–312. doi:10.1161/ATVBAHA.113.302302

    Article  CAS  PubMed  Google Scholar 

  2. Abraham NG, Kappas A (2008) Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60:79–127. doi:10.1124/pr.107.07104

    Article  CAS  PubMed  Google Scholar 

  3. Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL (1999) Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 274:26071–26078

    Article  CAS  PubMed  Google Scholar 

  4. Ali F, Ali NS, Bauer A, Boyle JJ, Hamdulay SS, Haskard DO, Randi AM, Mason JC (2010) PPARdelta and PGC1alpha act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress. Cardiovasc Res 85:701–710. doi:10.1093/cvr/cvp365

    Article  CAS  PubMed  Google Scholar 

  5. Allwood MA, Kinobe RT, Ballantyne L, Romanova N, Melo LG, Ward CA, Brunt KR, Simpson JA (2014) Heme oxygenase-1 overexpression exacerbates heart failure with aging and pressure overload but is protective against isoproterenol-induced cardiomyopathy in mice. Cardiovasc Pathol 23:231–237. doi:10.1016/j.carpath.2014.03.007

    Article  CAS  PubMed  Google Scholar 

  6. Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, Shen Y, Czech MP, Aouadi M (2014) Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab 19:162–171. doi:10.1016/j.cmet.2013.11.017

    Article  CAS  PubMed  Google Scholar 

  7. Amersi F, Buelow R, Kato H, Ke B, Coito AJ, Shen XD, Zhao D, Zaky J, Melinek J, Lassman CR, Kolls JK, Alam J, Ritter T, Volk HD, Farmer DG, Ghobrial RM, Busuttil RW, Kupiec-Weglinski JW (1999) Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest 104:1631–1639. doi:10.1172/JCI7903

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Aouadi M, Tencerova M, Vangala P, Yawe JC, Nicoloro SM, Amano SU, Cohen JL, Czech MP (2013) Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. Proc Natl Acad Sci USA 110:8278–8283. doi:10.1073/pnas.1300492110

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Ashrafian H, Czibik G, Bellahcene M, Aksentijevic D, Smith AC, Mitchell SJ, Dodd MS, Kirwan J, Byrne JJ, Ludwig C, Isackson H, Yavari A, Stottrup NB, Contractor H, Cahill TJ, Sahgal N, Ball DR, Birkler RI, Hargreaves I, Tennant DA, Land J, Lygate CA, Johannsen M, Kharbanda RK, Neubauer S, Redwood C, de Cabo R, Ahmet I, Talan M, Gunther UL, Robinson AJ, Viant MR, Pollard PJ, Tyler DJ, Watkins H (2012) Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway. Cell Metab 15:361–371. doi:10.1016/j.cmet.2012.01.017

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Bai Y, Cui W, Xin Y, Miao X, Barati MT, Zhang C, Chen Q, Tan Y, Cui T, Zheng Y, Cai L (2013) Prevention by sulforaphane of diabetic cardiomyopathy is associated with up-regulation of Nrf2 expression and transcription activation. J Mol Cell Cardiol 57:82–95. doi:10.1016/j.yjmcc.2013.01.008

    Article  CAS  PubMed  Google Scholar 

  11. Bak I, Szendrei L, Turoczi T, Papp G, Joo F, Das DK, de Leiris J, Der P, Juhasz B, Varga E, Bacskay I, Balla J, Kovacs P, Tosaki A (2003) Heme oxygenase-1-related carbon monoxide production and ventricular fibrillation in isolated ischemic/reperfused mouse myocardium. FASEB J 17:2133–2135. doi:10.1096/fj.03-0032fje

    CAS  PubMed  Google Scholar 

  12. Bansal S, Biswas G, Avadhani NG (2014) Mitochondria-targeted heme oxygenase-1 induces oxidative stress and mitochondrial dysfunction in macrophages, kidney fibroblasts and in chronic alcohol hepatotoxicity. Redox Biol 2:273–283. doi:10.1016/j.redox.2013.07.004

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Bao W, Song F, Li X, Rong S, Yang W, Zhang M, Yao P, Hao L, Yang N, Hu FB, Liu L (2010) Plasma heme oxygenase-1 concentration is elevated in individuals with type 2 diabetes mellitus. PLoS One 5:e12371. doi:10.1371/journal.pone.0012371

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM (2002) Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 105:293–296

    Article  CAS  PubMed  Google Scholar 

  15. Bilbija D, Gravning JA, Haugen F, Attramadal H, Valen G (2012) Protecting the heart through delivering DNA encoding for heme oxygenase-1 into skeletal muscle. Life Sci 91:828–836. doi:10.1016/j.lfs.2012.08.014

    Article  CAS  PubMed  Google Scholar 

  16. Biswas C, Shah N, Muthu M, La P, Fernando AP, Sengupta S, Yang G, Dennery PA (2014) Nuclear heme oxygenase-1 (HO-1) modulates subcellular distribution and activation of Nrf2 impacting metabolic and anti-oxidant defenses. J Biol Chem. doi:10.1074/jbc.M114.567685

    Google Scholar 

  17. Boengler K, Schulz R, Heusch G (2009) Loss of cardioprotection with ageing. Cardiovasc Res 83:247–261. doi:10.1093/cvr/cvp033

    Article  CAS  PubMed  Google Scholar 

  18. Bolisetty S, Traylor A, Zarjou A, Johnson MS, Benavides GA, Ricart K, Boddu R, Moore RD, Landar A, Barnes S, Darley-Usmar V, Agarwal A (2013) Mitochondria-targeted heme oxygenase-1 decreases oxidative stress in renal epithelial cells. Am J Physiol Renal Physiol 305:F255–F264. doi:10.1152/ajprenal.00160.2013

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Brunt KR, Tsuji MR, Lai JH, Kinobe RT, Durante W, Claycomb WC, Ward CA, Melo LG (2009) Heme oxygenase-1 inhibits pro-oxidant induced hypertrophy in HL-1 cardiomyocytes. Exp Biol Med (Maywood) 234:582–594. doi:10.3181/0810-RM-312

    Article  CAS  PubMed Central  Google Scholar 

  20. Bui AL, Horwich TB, Fonarow GC (2011) Epidemiology and risk profile of heart failure. Nat Rev Cardiol 8:30–41. doi:10.1038/nrcardio.2010.165

    Article  PubMed Central  PubMed  Google Scholar 

  21. Burgess A, Li M, Vanella L, Kim DH, Rezzani R, Rodella L, Sodhi K, Canestraro M, Martasek P, Peterson SJ, Kappas A, Abraham NG (2010) Adipocyte heme oxygenase-1 induction attenuates metabolic syndrome in both male and female obese mice. Hypertension 56:1124–1130. doi:10.1161/HYPERTENSIONAHA.110.151423

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, Shah SJ, Ahmed A, Bonow RO, Cleland JG, Cody RJ, Chioncel O, Collins SP, Dunnmon P, Filippatos G, Lefkowitz MP, Marti CN, McMurray JJ, Misselwitz F, Nodari S, O’Connor C, Pfeffer MA, Pieske B, Pitt B, Rosano G, Sabbah HN, Senni M, Solomon SD, Stockbridge N, Teerlink JR, Georgiopoulou VV, Gheorghiade M (2014) Developing therapies for heart failure with preserved ejection fraction: current state and future directions. JACC Heart Fail 2:97–112 (S2213-1779(14)00021-3)

    Article  PubMed  Google Scholar 

  23. Camhi SL, Alam J, Otterbein L, Sylvester SL, Choi AM (1995) Induction of heme oxygenase-1 gene expression by lipopolysaccharide is mediated by AP-1 activation. Am J Respir Cell Mol Biol 13:387–398. doi:10.1165/ajrcmb.13.4.7546768

    Article  CAS  PubMed  Google Scholar 

  24. Chen C, Huo R, Tong Y, Sheng Y, Liu HB, Gao X, Nakajima O, Yang BF, Dong DL (2011) Systemic heme oxygenase-1 transgenic overexpression aggravates pressure overload-induced cardiac hypertrophy in mice. Cell Physiol Biochem 28:25–32. doi:10.1159/000331710

    Article  PubMed  CAS  Google Scholar 

  25. Chen YH, Chau LY, Chen JW, Lin SJ (2008) Serum bilirubin and ferritin levels link heme oxygenase-1 gene promoter polymorphism and susceptibility to coronary artery disease in diabetic patients. Diabetes Care 31:1615–1620. doi:10.2337/dc07-2126

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Chen YH, Chau LY, Lin MW, Chen LC, Yo MH, Chen JW, Lin SJ (2004) Heme oxygenase-1 gene promotor microsatellite polymorphism is associated with angiographic restenosis after coronary stenting. Eur Heart J 25:39–47 (S0195668X03006845)

    Article  PubMed  CAS  Google Scholar 

  27. Chen YH, Lin SJ, Lin MW, Tsai HL, Kuo SS, Chen JW, Charng MJ, Wu TC, Chen LC, Ding YA, Pan WH, Jou YS, Chau LY (2002) Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients. Hum Genet 111:1–8. doi:10.1007/s00439-002-0769-4

    Article  CAS  PubMed  Google Scholar 

  28. Clark JE, Foresti R, Sarathchandra P, Kaur H, Green CJ, Motterlini R (2000) Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction. Am J Physiol Heart Circ Physiol 278:H643–H651

    CAS  PubMed  Google Scholar 

  29. Clark JE, Naughton P, Shurey S, Green CJ, Johnson TR, Mann BE, Foresti R, Motterlini R (2003) Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res 93:e2–e8. doi:10.1161/01.RES.0000084381.86567.08

    Article  CAS  PubMed  Google Scholar 

  30. Csongradi E, Docarmo JM, Dubinion JH, Vera T, Stec DE (2012) Chronic HO-1 induction with cobalt protoporphyrin (CoPP) treatment increases oxygen consumption, activity, heat production and lowers body weight in obese melanocortin-4 receptor-deficient mice. Int J Obes (Lond) 36:244–253. doi:10.1038/ijo.2011.78

    Article  CAS  Google Scholar 

  31. Czibik G (2010) Complex role of the HIF system in cardiovascular biology. J Mol Med (Berl) 88:1101–1111. doi:10.1007/s00109-010-0646-x

    Article  CAS  Google Scholar 

  32. Czibik G, Gravning J, Martinov V, Ishaq B, Knudsen E, Attramadal H, Valen G (2011) Gene therapy with hypoxia-inducible factor 1 alpha in skeletal muscle is cardioprotective in vivo. Life Sci 88:543–550. doi:10.1016/j.lfs.2011.01.006

    Article  CAS  PubMed  Google Scholar 

  33. Czibik G, Martinov V, Ruusalepp A, Sagave J, Skare O, Valen G (2009) In vivo remote delivery of DNA encoding for hypoxia-inducible factor 1 alpha reduces myocardial infarct size. Clin Transl Sci 2:33–40. doi:10.1111/j.1752-8062.2008.00077.x

    Article  CAS  PubMed  Google Scholar 

  34. Czibik G, Sagave J, Martinov V, Ishaq B, Sohl M, Sefland I, Carlsen H, Farnebo F, Blomhoff R, Valen G (2009) Cardioprotection by hypoxia-inducible factor 1 alpha transfection in skeletal muscle is dependent on haem oxygenase activity in mice. Cardiovasc Res 82:107–114

    Article  CAS  PubMed  Google Scholar 

  35. Czibik G, Steeples V, Yavari A, Ashrafian H (2014) Citric acid cycle intermediates in cardioprotection. Circ Cardiovasc Genet 7:711–719

    Article  CAS  Google Scholar 

  36. Czibik G, Wu Z, Berne GP, Tarkka M, Vaage J, Laurikka J, Jarvinen O, Valen G (2008) Human adaptation to ischemia by preconditioning or unstable angina: involvement of nuclear factor kappa B, but not hypoxia-inducible factor 1 alpha in the heart. Eur J Cardio-thoracic Surg 34:976–984. doi:10.1016/j.ejcts.2008.07.066

    Article  Google Scholar 

  37. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, Scrimieri F, Winter JM, Hruban RH, Iacobuzio-Donahue C, Kern SE, Blair IA, Tuveson DA (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475:106–109. doi:10.1038/nature10189

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Duckers HJ, Boehm M, True AL, Yet SF, San H, Park JL, Clinton Webb R, Lee ME, Nabel GJ, Nabel EG (2001) Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med 7:693–698. doi:10.1038/89068

    Article  CAS  PubMed  Google Scholar 

  39. Dulak J, Deshane J, Jozkowicz A, Agarwal A (2008) Heme oxygenase-1 and carbon monoxide in vascular pathobiology: focus on angiogenesis. Circulation 117:231–241. doi:10.1161/CIRCULATIONAHA.107.698316

    Article  CAS  PubMed  Google Scholar 

  40. Durante W (2010) Targeting heme oxygenase-1 in vascular disease. Curr Drug Targets 11:1504–1516 BSP/CDT/E-Pub/00146

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, Smith AV, Tobin MD, Verwoert GC, Hwang SJ, Pihur V, Vollenweider P, O’Reilly PF, Amin N, Bragg-Gresham JL, Teumer A, Glazer NL, Launer L, Zhao JH, Aulchenko Y, Heath S, Sober S, Parsa A, Luan J, Arora P, Dehghan A, Zhang F, Lucas G, Hicks AA, Jackson AU, Peden JF, Tanaka T, Wild SH, Rudan I, Igl W, Milaneschi Y, Parker AN, Fava C, Chambers JC, Fox ER, Kumari M, Go MJ, van der Harst P, Kao WH, Sjogren M, Vinay DG, Alexander M, Tabara Y, Shaw-Hawkins S, Whincup PH, Liu Y, Shi G, Kuusisto J, Tayo B, Seielstad M, Sim X, Nguyen KD, Lehtimaki T, Matullo G, Wu Y, Gaunt TR, Onland-Moret NC, Cooper MN, Platou CG, Org E, Hardy R, Dahgam S, Palmen J, Vitart V, Braund PS, Kuznetsova T, Uiterwaal CS, Adeyemo A, Palmas W, Campbell H, Ludwig B, Tomaszewski M, Tzoulaki I, Palmer ND, Aspelund T, Garcia M, Chang YP, O’Connell JR, Steinle NI, Grobbee DE, Arking DE, Kardia SL, Morrison AC, Hernandez D, Najjar S, McArdle WL, Hadley D, Brown MJ, Connell JM, Hingorani AD, Day IN, Lawlor DA, Beilby JP, Lawrence RW, Clarke R et al (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103–109. doi:10.1038/nature10405

    Article  CAS  PubMed  Google Scholar 

  42. Fillmore N, Mori J, Lopaschuk GD (2014) Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol 171:2080–2090. doi:10.1111/bph.12475

    Article  CAS  PubMed  Google Scholar 

  43. Foo RS, Siow RC, Brown MJ, Bennett MR (2006) Heme oxygenase-1 gene transfer inhibits angiotensin II-mediated rat cardiac myocyte apoptosis but not hypertrophy. J Cell Physiol 209:1–7. doi:10.1002/jcp.20723

    Article  CAS  PubMed  Google Scholar 

  44. Foresti R, Bains SK, Pitchumony TS, de Castro Bras LE, Drago F, Dubois-Rande JL, Bucolo C, Motterlini R (2013) Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells. Pharmacol Res 76:132–148. doi:10.1016/j.phrs.2013.07.010

    Article  CAS  PubMed  Google Scholar 

  45. Foresti R, Goatly H, Green CJ, Motterlini R (2001) Role of heme oxygenase-1 in hypoxia-reoxygenation: requirement of substrate heme to promote cardioprotection. Am J Physiol Heart Circ Physiol 281:H1976–H1984

    CAS  PubMed  Google Scholar 

  46. Freidja ML, Toutain B, Caillon A, Desquiret V, Lambert D, Loufrani L, Procaccio V, Henrion D (2011) Heme oxygenase 1 is differentially involved in blood flow-dependent arterial remodeling: role of inflammation, oxidative stress, and nitric oxide. Hypertension 58:225–231. doi:10.1161/HYPERTENSIONAHA.111.170266

    Article  CAS  PubMed  Google Scholar 

  47. Fujimoto H, Ohno M, Ayabe S, Kobayashi H, Ishizaka N, Kimura H, Yoshida K, Nagai R (2004) Carbon monoxide protects against cardiac ischemia–reperfusion injury in vivo via MAPK and Akt–eNOS pathways. Arterioscler Thromb Vasc Biol 24:1848–1853. doi:10.1161/01.ATV.0000142364.85911.0e

    Article  CAS  PubMed  Google Scholar 

  48. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367:1098–1107. doi:10.1056/NEJMoa1114287

    Article  CAS  PubMed  Google Scholar 

  49. Guo Y, Stein AB, Wu WJ, Tan W, Zhu X, Li QH, Dawn B, Motterlini R, Bolli R (2004) Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo. Am J Physiol Heart Circ Physiol 286:H1649–H1653. doi:10.1152/ajpheart.00971.2003

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Hausenloy DJ, Erik Botker H, Condorelli G, Ferdinandy P, Garcia-Dorado D, Heusch G, Lecour S, van Laake LW, Madonna R, Ruiz-Meana M, Schulz R, Sluijter JP, Yellon DM, Ovize M (2013) Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 98:7–27. doi:10.1093/cvr/cvt004

    Article  CAS  PubMed  Google Scholar 

  51. Heusch G (2013) Cardioprotection: chances and challenges of its translation to the clinic. Lancet 381:166–175. doi:10.1016/S0140-6736(12)60916-7

    Article  PubMed  Google Scholar 

  52. 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

    Article  PubMed  Google Scholar 

  53. Horsfall LJ, Nazareth I, Petersen I (2012) Cardiovascular events as a function of serum bilirubin levels in a large, statin-treated cohort. Circulation 126:2556–2564. doi:10.1161/CIRCULATIONAHA.112.114066

    Article  CAS  PubMed  Google Scholar 

  54. Hosick PA, AlAmodi AA, Storm MV, Gousset MU, Pruett BE, Gray W 3rd, Stout J, Stec DE (2014) Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet. Int J Obes (Lond) 38:132–139. doi:10.1038/ijo.2013.61

    Article  CAS  Google Scholar 

  55. Hu CM, Chen YH, Chiang MT, Chau LY (2004) Heme oxygenase-1 inhibits angiotensin II-induced cardiac hypertrophy in vitro and in vivo. Circulation 110:309–316. doi:10.1161/01.CIR.0000135475.35758.23

    Article  CAS  PubMed  Google Scholar 

  56. Hu CM, Lin HH, Chiang MT, Chang PF, Chau LY (2007) Systemic expression of heme oxygenase-1 ameliorates type 1 diabetes in NOD mice. Diabetes 56:1240–1247. doi:10.2337/db06-0495

    Article  CAS  PubMed  Google Scholar 

  57. Ichikawa T, Li J, Meyer CJ, Janicki JS, Hannink M, Cui T (2009) Dihydro-CDDO-trifluoroethyl amide (dh404), a novel Nrf2 activator, suppresses oxidative stress in cardiomyocytes. PLoS One 4:e8391. doi:10.1371/journal.pone.0008391

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  58. Issan Y, Kornowski R, Aravot D, Shainberg A, Laniado-Schwartzman M, Sodhi K, Abraham NG, Hochhauser E (2014) Heme Oxygenase-1 induction improves cardiac function following myocardial ischemia by reducing oxidative stress. PLoS One 9:e92246. doi:10.1371/journal.pone.0092246

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  59. Jais A, Einwallner E, Sharif O, Gossens K, Lu TT, Soyal SM, Medgyesi D, Neureiter D, Paier-Pourani J, Dalgaard K, Duvigneau JC, Lindroos-Christensen J, Zapf TC, Amann S, Saluzzo S, Jantscher F, Stiedl P, Todoric J, Martins R, Oberkofler H, Muller S, Hauser-Kronberger C, Kenner L, Casanova E, Sutterluty-Fall H, Bilban M, Miller K, Kozlov AV, Krempler F, Knapp S, Lumeng CN, Patsch W, Wagner O, Pospisilik JA, Esterbauer H (2014) Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man. Cell 158:25–40. doi:10.1016/j.cell.2014.04.043

    Article  CAS  PubMed  Google Scholar 

  60. Jeon EM, Choi HC, Lee KY, Chang KC, Kang YJ (2009) Hemin inhibits hypertensive rat vascular smooth muscle cell proliferation through regulation of cyclin D and p21. Arch Pharm Res 32:375–382. doi:10.1007/s12272-009-1310-2

    Article  CAS  PubMed  Google Scholar 

  61. Johnson RA, Lavesa M, DeSeyn K, Scholer MJ, Nasjletti A (1996) Heme oxygenase substrates acutely lower blood pressure in hypertensive rats. Am J Physiol 271:H1132–H1138

    CAS  PubMed  Google Scholar 

  62. Kaneda H, Ohno M, Taguchi J, Togo M, Hashimoto H, Ogasawara K, Aizawa T, Ishizaka N, Nagai R (2002) Heme oxygenase-1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors. Arterioscler Thromb Vasc Biol 22:1680–1685

    Article  CAS  PubMed  Google Scholar 

  63. Laakso M, Kuusisto J (2014) Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat Rev Endocrinol 10:293–302. doi:10.1038/nrendo.2014.29

    Article  CAS  PubMed  Google Scholar 

  64. Lakkisto P, Kyto V, Forsten H, Siren JM, Segersvard H, Voipio-Pulkki LM, Laine M, Pulkki K, Tikkanen I (2010) Heme oxygenase-1 and carbon monoxide promote neovascularization after myocardial infarction by modulating the expression of HIF-1alpha, SDF-1alpha and VEGF-B. Eur J Pharmacol 635:156–164. doi:10.1016/j.ejphar.2010.02.050

    Article  CAS  PubMed  Google Scholar 

  65. Lancel S, Montaigne D, Marechal X, Marciniak C, Hassoun SM, Decoster B, Ballot C, Blazejewski C, Corseaux D, Lescure B, Motterlini R, Neviere R (2012) Carbon monoxide improves cardiac function and mitochondrial population quality in a mouse model of metabolic syndrome. PLoS ONE 7:e41836. doi:10.1371/journal.pone.0041836

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Lavitrano M, Smolenski RT, Musumeci A, Maccherini M, Slominska E, Di Florio E, Bracco A, Mancini A, Stassi G, Patti M, Giovannoni R, Froio A, Simeone F, Forni M, Bacci ML, D’Alise G, Cozzi E, Otterbein LE, Yacoub MH, Bach FH, Calise F (2004) Carbon monoxide improves cardiac energetics and safeguards the heart during reperfusion after cardiopulmonary bypass in pigs. FASEB J 18:1093–1095. doi:10.1096/fj.03-0996fje

    CAS  PubMed  Google Scholar 

  67. Lavrovsky Y, Schwartzman ML, Levere RD, Kappas A, Abraham NG (1994) Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene. Proc Natl Acad Sci USA 91:5987–5991

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Lee PJ, Jiang BH, Chin BY, Iyer NV, Alam J, Semenza GL, Choi AM (1997) Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem 272:5375–5381

    Article  CAS  PubMed  Google Scholar 

  69. Li J, Ichikawa T, Villacorta L, Janicki JS, Brower GL, Yamamoto M, Cui T (2009) Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol 29:1843–1850. doi:10.1161/ATVBAHA.109.189480

    Article  CAS  PubMed  Google Scholar 

  70. Li M, Peterson S, Husney D, Inaba M, Guo K, Kappas A, Ikehara S, Abraham NG (2007) Long-lasting expression of HO-1 delays progression of type I diabetes in NOD mice. Cell Cycle 6:567–571 3917

    Article  CAS  PubMed  Google Scholar 

  71. Li Q, Guo Y, Ou Q, Wu WJ, Chen N, Zhu X, Tan W, Yuan F, Dawn B, Luo L, Hunt GN, Bolli R (2011) Gene transfer as a strategy to achieve permanent cardioprotection II: rAAV-mediated gene therapy with heme oxygenase-1 limits infarct size 1 year later without adverse functional consequences. Basic Res Cardiol 106:1367–1377. doi:10.1007/s00395-011-0208-6

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Li Volti G (2005) Letter regarding article by Hu et al, “heme oxygenase-1 inhibits angiotensin II-induced cardiac hypertrophy in vitro and in vivo”. Circulation 111:e100; author reply e100. doi:10.1161/01.CIR.0000155250.27345.02

  73. Libby P, Lichtman AH, Hansson GK (2013) Immune effec tor mechanisms implicated in atherosclerosis: from mice to humans. Immunity 38:1092–1104. doi:10.1016/j.immuni.2013.06.009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Lin HH, Chen YH, Chang PF, Lee YT, Yet SF, Chau LY (2008) Heme oxygenase-1 promotes neovascularization in ischemic heart by coinduction of VEGF and SDF-1. J Mol Cell Cardiol 45:44–55. doi:10.1016/j.yjmcc.2008.04.011

    Article  CAS  PubMed  Google Scholar 

  75. Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Bruck W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678–692. doi:10.1093/brain/awq386

    Article  PubMed  Google Scholar 

  76. 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 (20/2/207)

    Article  CAS  PubMed  Google Scholar 

  77. Liu X, Simpson JA, Brunt KR, Ward CA, Hall SR, Kinobe RT, Barrette V, Tse MY, Pang SC, Pachori AS, Dzau VJ, Ogunyankin KO, Melo LG (2007) Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction. Am J Physiol Heart Circ Physiol 293:H48–H59. doi:10.1152/ajpheart.00741.2006

    Article  CAS  PubMed  Google Scholar 

  78. Liu X, Wei J, Peng DH, Layne MD, Yet SF (2005) Absence of heme oxygenase-1 exacerbates myocardial ischemia/reperfusion injury in diabetic mice. Diabetes 54:778–784 (54/3/778)

    Article  CAS  PubMed  Google Scholar 

  79. Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184. doi:10.1172/JCI29881

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Mahabadi AA, Lehmann N, Mohlenkamp S, Kalsch H, Bauer M, Schulz R, Moebus S, Jockel KH, Erbel R, Heusch G (2014) Association of bilirubin with coronary artery calcification and cardiovascular events in the general population without known liver disease: the Heinz Nixdorf Recall study. Clin Res Cardiol 103:647–653. doi:10.1007/s00392-014-0697-z

    Article  CAS  PubMed  Google Scholar 

  81. Maines MD, Trakshel GM, Kutty RK (1986) Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. J Biol Chem 261:411–419

    CAS  PubMed  Google Scholar 

  82. Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y (1980) Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu 29:1–13

    CAS  PubMed  Google Scholar 

  83. Mansford KR, Opie L (1968) Comparison of metabolic abnormalities in diabetes mellitus induced by streptozotocin or by alloxan. Lancet 1:670–671

    Article  CAS  PubMed  Google Scholar 

  84. Mao X, Wang T, Liu Y, Irwin MG, Ou JS, Liao XL, Gao X, Xu Y, Ng KF, Vanhoutte PM, Xia Z (2013) N-acetylcysteine and allopurinol confer synergy in attenuating myocardial ischemia injury via restoring HIF-1alpha/HO-1 signaling in diabetic rats. PLoS One 8:e68949. doi:10.1371/journal.pone.0068949

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Matkovics B, Varga SI, Szabo L, Witas H (1982) The effect of diabetes on the activities of the peroxide metabolism enzymes. Horm Metab Res 14:77–79. doi:10.1055/s-2007-1018928

    Article  CAS  PubMed  Google Scholar 

  86. Melo LG, Agrawal R, Zhang L, Rezvani M, Mangi AA, Ehsan A, Griese DP, Dell’Acqua G, Mann MJ, Oyama J, Yet SF, Layne MD, Perrella MA, Dzau VJ (2002) Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene. Circulation 105:602–607

    Article  CAS  PubMed  Google Scholar 

  87. Mito S, Ozono R, Oshima T, Yano Y, Watari Y, Yamamoto Y, Brydun A, Igarashi K, Yoshizumi M (2008) Myocardial protection against pressure overload in mice lacking Bach1, a transcriptional repressor of heme oxygenase-1. Hypertension 51:1570–1577. doi:10.1161/HYPERTENSIONAHA.107.102566

    Article  CAS  PubMed  Google Scholar 

  88. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M, Motohashi H (2012) Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22:66–79. doi:10.1016/j.ccr.2012.05.016

    Article  CAS  PubMed  Google Scholar 

  89. Motterlini R, Foresti R (2014) Heme oxygenase-1 as a target for drug discovery. Antioxid Redox Signal 20:1810–1826. doi:10.1089/ars.2013.5658

    Article  CAS  PubMed  Google Scholar 

  90. Motterlini R, Gonzales A, Foresti R, Clark JE, Green CJ, Winslow RM (1998) Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo. Circ Res 83:568–577

    Article  CAS  PubMed  Google Scholar 

  91. Motterlini R, Otterbein LE (2010) The therapeutic potential of carbon monoxide. Nat Rev Drug Discov 9:728–743. doi:10.1038/nrd3228

    Article  CAS  PubMed  Google Scholar 

  92. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    Article  CAS  PubMed  Google Scholar 

  93. Namba F, Go H, Murphy JA, La P, Yang G, Sengupta S, Fernando AP, Yohannes M, Biswas C, Wehrli SL, Dennery PA (2014) Expression level and subcellular localization of heme oxygenase-1 modulates its cytoprotective properties in response to lung injury: a mouse model. PLoS ONE 9:e90936. doi:10.1371/journal.pone.0090936

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  94. Ndisang JF, Chibbar R, Lane N (2014) Heme oxygenase suppresses markers of heart failure and ameliorates cardiomyopathy in L-NAME-induced hypertension. Eur J Pharmacol 734C:23–34 (S0014-2999(14)00232-5)

    Article  CAS  Google Scholar 

  95. Neubauer S (2007) The failing heart–an engine out of fuel. N Engl J Med 356:1140–1151. doi:10.1056/NEJMra063052

    Article  PubMed  Google Scholar 

  96. Nishio Y, Kashiwagi A, Taki H, Shinozaki K, Maeno Y, Kojima H, Maegawa H, Haneda M, Hidaka H, Yasuda H, Horiike K, Kikkawa R (1998) Altered activities of transcription factors and their related gene expression in cardiac tissues of diabetic rats. Diabetes 47:1318–1325

    Article  CAS  PubMed  Google Scholar 

  97. Ockaili R, Natarajan R, Salloum F, Fisher BJ, Jones D, Fowler AA 3rd, Kukreja RC (2005) HIF-1 activation attenuates postischemic myocardial injury: role for heme oxygenase-1 in modulating microvascular chemokine generation. Am J Physiol Heart Circ Physiol 289:H542–H548. doi:10.1152/ajpheart.00089.2005

    Article  CAS  PubMed  Google Scholar 

  98. Oh DY, Morinaga H, Talukdar S, Bae EJ, Olefsky JM (2012) Increased macrophage migration into adipose tissue in obese mice. Diabetes 61:346–354. doi:10.2337/db11-0860

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Pachori AS, Melo LG, Hart ML, Noiseux N, Zhang L, Morello F, Solomon SD, Stahl GL, Pratt RE, Dzau VJ (2004) Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury. Proc Natl Acad Sci USA 101:12282–12287. doi:10.1073/pnas.0404616101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Piantadosi CA, Carraway MS, Babiker A, Suliman HB (2008) Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res 103:1232–1240. doi:10.1161/01.RES.0000338597.71702.ad

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Preda MB, Ronningen T, Burlacu A, Simionescu M, Moskaug JO, Valen G (2014) Remote transplantation of mesenchymal stem cells protects the heart against ischemia-reperfusion injury. Stem Cells. doi:10.1002/stem.1687

    PubMed  Google Scholar 

  102. Raj S, Franco VI, Lipshultz SE (2014) Anthracycline-induced cardiotoxicity: a review of pathophysiology, diagnosis, and treatment. Curr Treat Options Cardiovasc Med 16:315. doi:10.1007/s11936-014-0315-4

    Article  PubMed  Google Scholar 

  103. Rajasekaran NS, Connell P, Christians ES, Yan LJ, Taylor RP, Orosz A, Zhang XQ, Stevenson TJ, Peshock RM, Leopold JA, Barry WH, Loscalzo J, Odelberg SJ, Benjamin IJ (2007) Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. Cell 130:427–439 (S0092-8674(07)00849-5)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Rajasekaran NS, Varadharaj S, Khanderao GD, Davidson CJ, Kannan S, Firpo MA, Zweier JL, Benjamin IJ (2011) Sustained activation of nuclear erythroid 2-related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice. Antioxid Redox Signal 14:957–971. doi:10.1089/ars.2010.3587

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Seddon M, Looi YH, Shah AM (2007) Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 93:903–907 (hrt.2005.068270)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Shinomiya M, Nadano S, Shinomiya H, Onji M (2000) In situ characterization of dendritic cells occurring in the islets of nonobese diabetic mice during the development of insulitis. Pancreas 20:290–296

    Article  CAS  PubMed  Google Scholar 

  107. Shu T, Zeng B, Ren X, Li Y (2010) HO-1 modified mesenchymal stem cells modulate MMPs/TIMPs system and adverse remodeling in infarcted myocardium. Tissue Cell 42:217–222. doi:10.1016/j.tice.2010.04.004

    Article  CAS  PubMed  Google Scholar 

  108. Singh A, Happel C, Manna SK, Acquaah-Mensah G, Carrerero J, Kumar S, Nasipuri P, Krausz KW, Wakabayashi N, Dewi R, Boros LG, Gonzalez FJ, Gabrielson E, Wong KK, Girnun G, Biswal S (2013) Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J Clin Invest 123:2921–2934. doi:10.1172/JCI66353

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Stec DE, Drummond HA, Gousette MU, Storm MV, Abraham NG, Csongradi E (2012) Expression of heme oxygenase-1 in thick ascending loop of henle attenuates angiotensin II-dependent hypertension. J Am Soc Nephrol 23:834–841. doi:10.1681/ASN.2011050455

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Stein AB, Bolli R, Dawn B, Sanganalmath SK, Zhu Y, Wang OL, Guo Y, Motterlini R, Xuan YT (2012) Carbon monoxide induces a late preconditioning-mimetic cardioprotective and antiapoptotic milieu in the myocardium. J Mol Cell Cardiol 52:228–236. doi:10.1016/j.yjmcc.2011.11.005

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. Stein AB, Guo Y, Tan W, Wu WJ, Zhu X, Li Q, Luo C, Dawn B, Johnson TR, Motterlini R, Bolli R (2005) Administration of a CO-releasing molecule induces late preconditioning against myocardial infarction. J Mol Cell Cardiol 38:127–134. doi:10.1016/j.yjmcc.2004.10.006

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  112. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235:1043–1046

    Article  CAS  PubMed  Google Scholar 

  113. Suliman HB, Carraway MS, Ali AS, Reynolds CM, Welty-Wolf KE, Piantadosi CA (2007) The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. J Clin Invest 117:3730–3741. doi:10.1172/JCI32967

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Taille C, El-Benna J, Lanone S, Dang MC, Ogier-Denis E, Aubier M, Boczkowski J (2004) Induction of heme oxygenase-1 inhibits NAD(P)H oxidase activity by down-regulating cytochrome b558 expression via the reduction of heme availability. J Biol Chem 279:28681–28688. doi:10.1074/jbc.M310661200

    Article  CAS  PubMed  Google Scholar 

  115. Takimoto E, Kass DA (2007) Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 49:241–248. doi:10.1161/01.HYP.0000254415.31362.a7

    Article  CAS  PubMed  Google Scholar 

  116. Tang YL, Tang Y, Zhang YC, Agarwal A, Kasahara H, Qian K, Shen L, Phillips MI (2005) A hypoxia-inducible vigilant vector system for activating therapeutic genes in ischemia. Gene Ther 12:1163–1170 (3302513)

    Article  CAS  PubMed  Google Scholar 

  117. Tang YL, Tang Y, Zhang YC, Qian K, Shen L, Phillips MI (2005) Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J Am Coll Cardiol 46:1339–1350 (S0735-1097(05)01656-6)

    Article  CAS  PubMed  Google Scholar 

  118. Tang YL, Tang Y, Zhang YC, Qian K, Shen L, Phillips MI (2004) Protection from ischemic heart injury by a vigilant heme oxygenase-1 plasmid system. Hypertension 43:746–751. doi:10.1161/01.HYP.0000120152.27263.87

    Article  CAS  PubMed  Google Scholar 

  119. Tongers J, Fiedler B, Konig D, Kempf T, Klein G, Heineke J, Kraft T, Gambaryan S, Lohmann SM, Drexler H, Wollert KC (2004) Heme oxygenase-1 inhibition of MAP kinases, calcineurin/NFAT signaling, and hypertrophy in cardiac myocytes. Cardiovasc Res 63:545–552. doi:10.1016/j.cardiores.2004.04.015

    Article  CAS  PubMed  Google Scholar 

  120. Tsubokawa T, Yagi K, Nakanishi C, Zuka M, Nohara A, Ino H, Fujino N, Konno T, Kawashiri MA, Ishibashi-Ueda H, Nagaya N, Yamagishi M (2010) Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia. Am J Physiol Heart Circ Physiol 298:H1320–H1329. doi:10.1152/ajpheart.01330.2008

    Article  CAS  PubMed  Google Scholar 

  121. Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, de Cabo R, Csiszar A (2010) Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 299:H18–H24. doi:10.1152/ajpheart.00260.2010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Ungvari Z, Bailey-Downs L, Gautam T, Jimenez R, Losonczy G, Zhang C, Ballabh P, Recchia FA, Wilkerson DC, Sonntag WE, Pearson K, de Cabo R, Csiszar A (2011) Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am J Physiol Heart Circ Physiol 300:H1133–H1140. doi:10.1152/ajpheart.00402.2010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  123. Vera T, Kelsen S, Stec DE (2008) Kidney-specific induction of heme oxygenase-1 prevents angiotensin II hypertension. Hypertension 52:660–665. doi:10.1161/HYPERTENSIONAHA.108.114884

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  124. Verma A, Hirsch DJ, Glatt CE, Ronnett GV, Snyder SH (1993) Carbon monoxide: a putative neural messenger. Science 259:381–384

    Article  CAS  PubMed  Google Scholar 

  125. Vulapalli SR, Chen Z, Chua BH, Wang T, Liang CS (2002) Cardioselective overexpression of HO-1 prevents I/R-induced cardiac dysfunction and apoptosis. Am J Physiol Heart Circ Physiol 283:H688–H694. doi:10.1152/ajpheart.00133.2002

    CAS  PubMed  Google Scholar 

  126. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  127. Watkins H, Ashrafian H, Redwood C (2011) Inherited cardiomyopathies. N Engl J Med 364:1643–1656. doi:10.1056/NEJMra0902923

    Article  CAS  PubMed  Google Scholar 

  128. Wende AR, Symons JD, Abel ED (2012) Mechanisms of lipotoxicity in the cardiovascular system. Curr Hypertens Rep 14:517–531. doi:10.1007/s11906-012-0307-2

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  129. Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, Wabitsch M, O’Brien PE, Harrison LC (2010) Pro-inflammatory CD11c + CD206 + adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 59:1648–1656. doi:10.2337/db09-0287

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  130. Wiesel P, Patel AP, Carvajal IM, Wang ZY, Pellacani A, Maemura K, DiFonzo N, Rennke HG, Layne MD, Yet SF, Lee ME, Perrella MA (2001) Exacerbation of chronic renovascular hypertension and acute renal failure in heme oxygenase-1-deficient mice. Circ Res 88:1088–1094

    Article  CAS  PubMed  Google Scholar 

  131. Wohaieb SA, Godin DV (1987) Alterations in free radical tissue-defense mechanisms in streptozocin-induced diabetes in rat effects of insulin treatment. Diabetes 36:1014–1018

    Article  CAS  PubMed  Google Scholar 

  132. Worou ME, Belmokhtar K, Bonnet P, Vourc’h P, Machet MC, Khamis G, Eder V (2011) Hemin decreases cardiac oxidative stress and fibrosis in a rat model of systemic hypertension via PI3K/Akt signalling. Cardiovasc Res 91:320–329. doi:10.1093/cvr/cvr072

    Article  CAS  PubMed  Google Scholar 

  133. Wu ML, Ho YC, Yet SF (2011) A central role of heme oxygenase-1 in cardiovascular protection. Antioxid Redox Signal 15:1835–1846. doi:10.1089/ars.2010.3726

    Article  CAS  PubMed  Google Scholar 

  134. Xing Y, Niu T, Wang W, Li J, Li S, Janicki JS, Ruiz S, Meyer CJ, Wang XL, Tang D, Zhao Y, Cui T (2012) Triterpenoid dihydro-CDDO-trifluoroethyl amide protects against maladaptive cardiac remodeling and dysfunction in mice: a critical role of Nrf2. PLoS One 7:e44899. doi:10.1371/journal.pone.0044899

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  135. Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135. doi:10.1056/NEJMra071667

    Article  CAS  PubMed  Google Scholar 

  136. 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

    Article  CAS  PubMed  Google Scholar 

  137. Yoshida T, Biro P, Cohen T, Muller RM, Shibahara S (1988) Human heme oxygenase cDNA and induction of its mRNA by hemin. Eur J Biochem 171:457–461

    Article  CAS  PubMed  Google Scholar 

  138. 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

    Article  CAS  PubMed  Google Scholar 

  139. Yun L, Xiaoli L, Qi Z, Laiyuan W, Xiangfeng L, Chong S, Jianfeng H, Shufeng C, Hongfan L, Gu D (2009) Association of an intronic variant of the heme oxygenase-1 gene with hypertension in northern Chinese Han population. Clin Exp Hypertens 31:534–543. doi:10.3109/10641960902825461

    Article  CAS  PubMed  Google Scholar 

  140. Zeng B, Lin G, Ren X, Zhang Y, Chen H (2010) Over-expression of HO-1 on mesenchymal stem cells promotes angiogenesis and improves myocardial function in infarcted myocardium. J Biomed Sci 17:80. doi:10.1186/1423-0127-17-80

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  141. Zeng B, Ren X, Lin G, Zhu C, Chen H, Yin J, Jiang H, Yang B, Ding D (2008) Paracrine action of HO-1-modified mesenchymal stem cells mediates cardiac protection and functional improvement. Cell Biol Int 32:1256–1264. doi:10.1016/j.cellbi.2008.07.010

    Article  CAS  PubMed  Google Scholar 

  142. Zhao Y, Zhang L, Qiao Y, Zhou X, Wu G, Wang L, Peng Y, Dong X, Huang H, Si L, Zhang X, Li J, Wang W, Zhou L, Gao X (2013) Heme oxygenase-1 prevents cardiac dysfunction in streptozotocin-diabetic mice by reducing inflammation, oxidative stress, apoptosis and enhancing autophagy. PLoS One 8:e75927. doi:10.1371/journal.pone.0075927

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

In the late preparation of the paper our co-author Prof. Guro Valen passed away. GC is supported by DHU A-TVB, APHP, France. GV was a recipient of grants from the National Association for Public Health and the University of Oslo. RM is supported by a Blanc II International Grant from the Agence Nationale de la Recherche (MITO-CO), the Fonds National de la Recherche Luxembourg, a Multidisciplinary Grant from UPEC and the AREMCAR Foundation.

Conflict of interest

On behalf of all authors, the corresponding authors state that there is no conflict of interest.

Author information

Authors and Affiliations

  1. INSERM U955, Equipe 8, Faculty of Medicine, DHU A-TVB, Hôpital Henri Mondor, APHP, Creteil, University of Paris-Est, 3rd Floor, room 3006, Paris, France

    Gabor Czibik, Geneviéve Derumeaux & Daigo Sawaki

  2. INSERM U955, Equipe 3, Faculty of Medicine, DHU A-TVB, Hôpital Henri Mondor, APHP, Creteil, University of Paris-Est, 3rd Floor, room 3014/3060, Paris, France

    Roberto Motterlini

  3. Deptartment Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

    Guro Valen

Authors
  1. Gabor Czibik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Geneviéve Derumeaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daigo Sawaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guro Valen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roberto Motterlini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Gabor Czibik or Roberto Motterlini.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-014-0450-9

Keywords

Search

Navigation