{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T13:43:03Z","timestamp":1773236583377,"version":"3.50.1"},"reference-count":43,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":3059,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>We and others have previously demonstrated that heme oxygenase 1 (HO-1) induction by acute hemin administration exerts cardioprotective effects. Here, we developed a rat model of heart failure to investigate whether a long-term induction of HO-1 by chronic hemin administration exerted protective effects. Sprague Dawley rats that underwent permanent ligation of the left coronary artery were closely monitored for survival rate analysis and sacrificed on day 28 post-operation. Administration of hemin (4 mg\/kg body weight) every other day for 4 weeks induced a massive increase in HO-1 expression and activity, as shown by the increased levels of the two main metabolic products of heme degradation, bilirubin and carbon monoxide (CO). These effects were associated with significant improvement in survival and reduced the extension of myocardial damage. The ischemic hearts of the hemin-treated animals displayed reduced oxidative stress and apoptosis in comparison with the non-treated rats, as shown by the decreased levels of lipid peroxidation, free-radical-induced DNA damage, caspase-3 activity and Bax expression. Besides, chronic HO-1 activation suppressed the elevated levels of myeloperoxidase (MPO) activity, interleukin 1\u03b2 (IL-1\u03b2) production and tumor necrosis factor-\u03b1 (TNF\u03b1) production that were evoked by the ischemic injury, and increased the plasma level of the anti-inflammatory cytokine IL-10. Interestingly, HO-1 inhibitor zinc protoporphyrin IX (ZnPP-IX; 1 mg\/kg) lowered bilirubin and CO concentrations to control values, thus abolishing all the cardioprotective effects of hemin. In conclusion, the results demonstrate that chronic HO-1 activation by prolonged administration of hemin improves survival and exerts protective effects in a rat model of myocardial ischemia by exerting a potent antioxidant activity and disrupting multiple levels of the apoptotic and inflammatory cascade.<\/jats:p>","DOI":"10.1242\/dmm.011528","type":"journal-article","created":{"date-parts":[[2013,4,17]],"date-time":"2013-04-17T03:11:59Z","timestamp":1366168319000},"source":"Crossref","is-referenced-by-count":29,"title":["Beneficial effect of prolonged heme oxygenase 1 activation in a rat model of chronic heart failure"],"prefix":"10.1242","author":[{"given":"Massimo","family":"Collino","sequence":"first","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, Turin, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Pini","sequence":"additional","affiliation":[{"name":"Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niccol\u00f2","family":"Mugelli","sequence":"additional","affiliation":[{"name":"Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosanna","family":"Mastroianni","sequence":"additional","affiliation":[{"name":"Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele","family":"Bani","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Fantozzi","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, Turin, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Papucci","sequence":"additional","affiliation":[{"name":"Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marilena","family":"Fazi","sequence":"additional","affiliation":[{"name":"Department of Physiopathology, Surgery Unit, University of Florence, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuela","family":"Masini","sequence":"additional","affiliation":[{"name":"Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2013,1,1]]},"reference":[{"key":"2021042501092641500_b1-0061012","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2005.03.010","article-title":"Heme oxygenase and the cardiovascular-renal system","volume":"39","author":"Abraham","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"2021042501092641500_b2-0061012","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1042\/bj2580617","article-title":"The mechanism of initiation of lipid peroxidation. Evidence against a requirement for an iron(II)-iron(III) complex","volume":"258","author":"Aruoma","year":"1989","journal-title":"Biochem. J."},{"key":"2021042501092641500_b3-0061012","first-page":"1367","article-title":"Relaxin protects against myocardial injury caused by ischemia and reperfusion in rat heart","volume":"152","author":"Bani","year":"1998","journal-title":"Am. J. Pathol."},{"key":"2021042501092641500_b4-0061012","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1093\/clinchem\/40.10.1987","article-title":"Is bilirubin protective against coronary artery disease?","volume":"40","author":"Breimer","year":"1994","journal-title":"Clin. Chem."},{"key":"2021042501092641500_b5-0061012","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1111\/j.1600-6143.2005.00742.x","article-title":"Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction","volume":"5","author":"Brennan","year":"2005","journal-title":"Am. J. Transplant."},{"key":"2021042501092641500_b6-0061012","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1084\/jem.192.7.1015","article-title":"Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis","volume":"192","author":"Brouard","year":"2000","journal-title":"J. Exp. Med."},{"key":"2021042501092641500_b7-0061012","doi-asserted-by":"crossref","first-page":"33720","DOI":"10.1074\/jbc.M112.385542","article-title":"The heme oxygenase 1 inducer (CoPP) protects human cardiac stem cells against apoptosis through activation of the extracellular signal-regulated kinase (ERK)\/NRF2 signaling pathway and cytokine release","volume":"287","author":"Cai","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2021042501092641500_b8-0061012","doi-asserted-by":"crossref","first-page":"H2313","DOI":"10.1152\/ajpheart.2001.280.5.H2313","article-title":"Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I\/R injury in transgenic mice","volume":"280","author":"Chen","year":"2001","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2021042501092641500_b9-0061012","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1097\/SHK.0b013e318164e762","article-title":"Treatment with the glycogen synthase kinase-3beta inhibitor, TDZD-8, affects transient cerebral ischemia\/reperfusion injury in the rat hippocampus","volume":"30","author":"Collino","year":"2008","journal-title":"Shock"},{"key":"2021042501092641500_b10-0061012","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1124\/jpet.111.185348","article-title":"Therapeutic potential of pegylated hemin for reactive oxygen species-related diseases via induction of heme oxygenase-1: results from a rat hepatic ischemia\/reperfusion injury model","volume":"339","author":"Fang","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021042501092641500_b11-0061012","doi-asserted-by":"crossref","first-page":"e33","DOI":"10.1159\/000313828","article-title":"Hemeoxygenase-1 and renal ischaemia-reperfusion injury","volume":"115","author":"Ferenbach","year":"2010","journal-title":"Nephron Exp. Nephrol."},{"key":"2021042501092641500_b12-0061012","first-page":"393","article-title":"Protection from cardiac injury by induction of heme oxygenase-1 and nitric oxide synthase in a focal ischaemia-reperfusion model","volume":"51","author":"Giannini","year":"2005","journal-title":"Cell Mol Biol"},{"key":"2021042501092641500_b13-0061012","doi-asserted-by":"crossref","first-page":"6977","DOI":"10.1021\/bi020647r","article-title":"Mechanism of low-density lipoprotein oxidation by hemoglobin-derived iron","volume":"42","author":"Grinshtein","year":"2003","journal-title":"Biochemistry"},{"key":"2021042501092641500_b14-0061012","doi-asserted-by":"crossref","first-page":"2622","DOI":"10.4049\/jimmunol.175.4.2622","article-title":"Heat shock protein-70 mediates the cytoprotective effect of carbon monoxide: involvement of p38 beta MAPK and heat shock factor-1","volume":"175","author":"Kim","year":"2005","journal-title":"J. Immunol."},{"key":"2021042501092641500_b15-0061012","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.toxlet.2005.03.004","article-title":"Free heme toxicity and its detoxification systems in human","volume":"157","author":"Kumar","year":"2005","journal-title":"Toxicol. Lett."},{"key":"2021042501092641500_b16-0061012","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1080\/00365510802474392","article-title":"The heme oxygenase inducer hemin protects against cardiac dysfunction and ventricular fibrillation in ischaemic\/reperfused rat hearts: role of connexin 43","volume":"69","author":"Lakkisto","year":"2009","journal-title":"Scand. J. Clin. Lab. Invest."},{"key":"2021042501092641500_b17-0061012","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0167-4889(94)90067-1","article-title":"Heme oxygenase and oxidative stress. Evidence of involvement of bilirubin as physiological protector against oxidative damage","volume":"1223","author":"Llesuy","year":"1994","journal-title":"Biochim. Biophys. Acta"},{"key":"2021042501092641500_b18-0061012","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1146\/annurev.pharmtox.37.1.517","article-title":"The heme oxygenase system: a regulator of second messenger gases","volume":"37","author":"Maines","year":"1997","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"2021042501092641500_b19-0061012","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/sj.bjp.0704774","article-title":"Protective effects of M40403, a selective superoxide dismutase mimetic, in myocardial ischaemia and reperfusion injury in vivo","volume":"136","author":"Masini","year":"2002","journal-title":"Br. J. Pharmacol."},{"key":"2021042501092641500_b20-0061012","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1177\/15353702-0322805-25","article-title":"Heme oxygenase-1 and the ischemia-reperfusion injury in the rat heart","volume":"228","author":"Masini","year":"2003","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"2021042501092641500_b21-0061012","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.freeradbiomed.2005.04.006","article-title":"Reduction of antigen-induced respiratory abnormalities and airway inflammation in sensitized guinea pigs by a superoxide dismutase mimetic","volume":"39","author":"Masini","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"2021042501092641500_b22-0061012","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1093\/clinchem\/46.11.1723","article-title":"Association of serum bilirubin concentration with risk of coronary artery disease","volume":"46","author":"Mayer","year":"2000","journal-title":"Clin. Chem."},{"key":"2021042501092641500_b23-0061012","doi-asserted-by":"crossref","first-page":"36993","DOI":"10.1074\/jbc.M302942200","article-title":"Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1","volume":"278","author":"Morse","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021042501092641500_b24-0061012","doi-asserted-by":"crossref","first-page":"8144","DOI":"10.1073\/pnas.96.14.8144","article-title":"Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy","volume":"96","author":"Narula","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042501092641500_b25-0061012","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1681\/ASN.2011101019","article-title":"Vasculature and kidney complications in sickle cell disease","volume":"23","author":"Nath","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021042501092641500_b26-0061012","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1038\/sj.bjp.0704427","article-title":"Haeme oxygenase-1 and cardiac anaphylaxis","volume":"134","author":"Ndisang","year":"2001","journal-title":"Br. J. Pharmacol."},{"key":"2021042501092641500_b27-0061012","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.trsl.2011.01.003","article-title":"Hsp60 and heme oxygenase-1 (Hsp32) in acute myocardial infarction","volume":"157","author":"Novo","year":"2011","journal-title":"Transl. Res."},{"key":"2021042501092641500_b28-0061012","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/74680","article-title":"Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway","volume":"6","author":"Otterbein","year":"2000","journal-title":"Nat. Med."},{"key":"2021042501092641500_b29-0061012","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/CRD.0b013e31819d813a","article-title":"Targeting heme oxygenase: therapeutic implications for diseases of the cardiovascular system","volume":"17","author":"Peterson","year":"2009","journal-title":"Cardiol. Rev."},{"key":"2021042501092641500_b30-0061012","doi-asserted-by":"crossref","first-page":"L312","DOI":"10.1152\/ajplung.2000.278.2.L312","article-title":"Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts","volume":"278","author":"Petrache","year":"2000","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2021042501092641500_b31-0061012","doi-asserted-by":"crossref","first-page":"25719","DOI":"10.1074\/jbc.272.41.25719","article-title":"Biochemical characteristics of caspases-3, -6, -7, and -8","volume":"272","author":"Stennicke","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021042501092641500_b32-0061012","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1161\/01.HYP.0000120152.27263.87","article-title":"Protection from ischemic heart injury by a vigilant heme oxygenase-1 plasmid system","volume":"43","author":"Tang","year":"2004","journal-title":"Hypertension"},{"key":"2021042501092641500_b33-0061012","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/ajg.2009.2","article-title":"Increased plasma carbon monoxide in patients with viral cirrhosis and hyperdynamic circulation","volume":"104","author":"Tarquini","year":"2009","journal-title":"Am. J. Gastroenterol."},{"key":"2021042501092641500_b34-0061012","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.pharmthera.2005.10.017","article-title":"Heme as key regulator of major mammalian cellular functions: molecular, cellular, and pharmacological aspects","volume":"111","author":"Tsiftsoglou","year":"2006","journal-title":"Pharmacol. Ther."},{"key":"2021042501092641500_b35-0061012","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1126\/science.7678352","article-title":"Carbon monoxide: a putative neural messenger","volume":"259","author":"Verma","year":"1993","journal-title":"Science"},{"key":"2021042501092641500_b36-0061012","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s004240050398","article-title":"The direct effect of carbon monoxide on KCa channels in vascular smooth muscle cells","volume":"434","author":"Wang","year":"1997","journal-title":"Pflugers Arch."},{"key":"2021042501092641500_b37-0061012","doi-asserted-by":"crossref","first-page":"3809","DOI":"10.4049\/jimmunol.0712437","article-title":"The heme oxygenase-1\/carbon monoxide pathway suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1","volume":"182","author":"Wang","year":"2009","journal-title":"J. Immunol."},{"key":"2021042501092641500_b38-0061012","first-page":"1912","article-title":"Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart","volume-title":"Circulation","author":"Wang","year":"2010"},{"key":"2021042501092641500_b39-0061012","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.jss.2008.07.044","article-title":"HO-1 activation can attenuate cardiomyocytic apoptosis via inhibition of NF-kappaB and AP-1 translocation following cardiac global ischemia and reperfusion","volume":"155","author":"Yeh","year":"2009","journal-title":"J. Surg. Res."},{"key":"2021042501092641500_b40-0061012","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1161\/hh1401.093314","article-title":"Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice","volume":"89","author":"Yet","year":"2001","journal-title":"Circ. Res."},{"key":"2021042501092641500_b41-0061012","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1161\/01.CIR.103.12.1695","article-title":"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","volume":"103","author":"Yoshida","year":"2001","journal-title":"Circulation"},{"key":"2021042501092641500_b42-0061012","doi-asserted-by":"crossref","first-page":"22061","DOI":"10.1074\/jbc.M301858200","article-title":"Carbon monoxide modulates Fas\/Fas ligand, caspases, and Bcl-2 family proteins via the p38alpha mitogen-activated protein kinase pathway during ischemia-reperfusion lung injury","volume":"278","author":"Zhang","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021042501092641500_b43-0061012","doi-asserted-by":"crossref","first-page":"G607","DOI":"10.1152\/ajpgi.00055.2005","article-title":"Carbon monoxide protects against the development of experimental necrotizing enterocolitis","volume":"289","author":"Zuckerbraun","year":"2005","journal-title":"Am. J. Physiol. Gastrointest. 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