肢体缺血再灌注大鼠心肌中的氧化应激及HO-1mRNA的表达
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摘要
背景与目的:肢体缺血再灌注损伤临床上极为常见,外周血管手术、肢体的创伤、断肢再植术、血栓形成、腹主动脉瘤手术、挤压综合征等均可引起肢体缺血再灌注损伤。近年研究发现,肢体缺血再灌注损伤不仅影响局部缺血组织的存活和功能,而且还可造成全身炎症反应综合征,累及心、肝、肺、肾、小肠、脑等远隔器官、导致多器官功能受损,其中以心血管系统的损伤最为重要。目前对肢体缺血后所致的肺,脑,肝,肠损伤机制的研究较多,对骨胳肌缺血再灌注所致心肌损伤病理生理机制,至今尚未完全阐明,大量研究表明:严重的肢体缺血再灌注损伤可导致应激性的高血压,应激性心律失常,应激性心肌缺血,心功能不全等,血红素加氧酶-1(heme oxygenase-1,HO-1)是目前发现的受最多因素诱导的应激蛋白。这些刺激的共同点是能造成氧化应激。HO-1具有抗炎、抗细胞凋亡、抗增殖、抗氧化的性质,还有免疫应答等方面具有重要的作用,并成为近几年的研究热点。
本实验应用止血带构建大鼠下肢缺血再灌注模型,观察肢体缺血再灌注后心肌病理学改变,氧化应激机制及诱导型血红素氧化酶(HO-1)的表达来说明心肌的损伤及自身保护机制。本实验分为两个部分:一,观察肢体缺血再灌注后心肌的损伤变化,并了解氧化应激在肢体缺血再灌注后继发的心肌损伤中的作用。二,观察内源性HO-1在肢体缺血再灌注后心肌中的表达变化的规律及其意义。
方法:本实验应用止血带捆扎大鼠下肢来构造肢体缺血再灌注模型,将实验的大鼠随机分为七组。即:正常组,缺血4小时再灌注2小时组,再灌注4小时组,再灌注6小时组,再灌注8小时组,再灌注16小时组,再灌注24小时组。第一部分实验:应用光镜观察心肌组织的病理变化;分别测定血清及心肌组织中的丙二醛(MDA)含量、总超氧化物歧化酶(T-SOD)活力及髓过氧化物酶(MPO)活性。第二部分实验:应用反转录—多聚酶链反应(RT-PCR)检测心肌HO-1mRNA表达的变化规律。
结果:缺血再灌注4,6小时,心肌细胞明显肿胀,肌间隙增宽,小血管充血明显,肌间隙内可见大量红细胞漏出,肌间隙有核细胞明显增多,再灌注24小时上述改变减轻。与正常组比较,血浆MDA及心肌MDA:缺血再灌注各组均明显升高(P＜0.01),再灌注4h达高峰;血浆SOD:缺血再灌注各组均明显下降(P＜0.01),再灌注4小时达最低值,心肌SOD:再灌注各组均明显下降(P＜0.01),再灌注8小时达最低值;血浆及心肌MPO:缺血再灌注2h～8h出现明显升高(P＜0.01),血浆MPO 4h达高峰,心肌MPO 6h达高峰,16,24h下降。肢体缺血再灌注可诱导HO-1mRNA在心肌表达上调,与正常组比较,再灌注2h,HO-1mRNA表达无显著变化(P＞0.05);再灌注4h,6h,8h,16h,24h后HO-1表达显著增强(P＜0.01),并在16h达高峰。
结论:肢体缺血再灌注可造成心肌损伤,再灌注4-6小时心肌损伤最重,全身及心肌局部的炎细胞聚集活化,炎性因子的激活和过度的氧化应激及氧化抗氧化失衡是肢体缺血再灌注致心肌损伤的机制,机体存在自身保护机制,活性氧族及炎性因子能上调HO-1的表达,对抗氧化应激,从而发挥心肌细胞保护作用。
Objective and background:ischemical reperfusion injury of limb is a common pathophysiological phenomenon clinically.Ischemia of the limbs is a unavoidable occurrence during peripheral vasculai surgery, insult of limbs、thrombogenesis、abdominal aneurysm surgery, replantation of extremities,peripheral vascular injury or crushing syndrome.Recent studies have shown that limb IR can trigger a systemic inflammatory response syndrome(SIRS).It causes not only local tissue injury,but also remote organs dysfunction including heart,liver,lung,kindy and small intestine.clinical studies suggest that the heart is at high risk in the setting of sirs.the mechanism of acute myocardial injury following limb IR is very complicated,up to now,not completely elucidated yet.a great quantity of study indicate that severe ischemical reperfusion injury of limb can induce irritable high blood pressure,arrhythmia,myocardial ischemia and cardia insufficiency,heme oxygenase-1 is a ubiquitous stress protein and is induced in many cell types by various stimuli.the this stimuli all can induce oxidative stress.The protective effects of HO-1 is very important via its antiinflammatory,antiapoptotic,antiproliferative, and antioxidant properties,as well as its effects on the immune response. In the present study,we have established the model of bilateral hindlimb ischemia and reperfusion in rats by using a tourniquet.To explain the mechanism of myocardial injury and autoprotection by observing pathologic change of myocardium,the mechanism of oxidative stress and the expression of HO-1mRNA..our experiment is divided into two parts:Firstly,we explore the role of oxidative stress in the myocardial injury following the limb ischemical reperfusion injury by observing change of myocardium.secondly,we are to ascertain the protective effects of endogenous HO-lon the myocardial injury during the limb ischemical reperfusion.
Method:we have established the model of bilateral hindlimb ischemia and reperfusion in rats by using a tourniquet.the experimental rats were divided to 7 groups randomly.Igroup:Normal group;Ⅱgroup:a group of animals were subjected to suffer ischemic 4h and reperfusion 2h,Ⅲgroup:ischemic 4h and reperfusion 4h;Ⅳgroup:ischemic 4h and reperfusion 6h;Ⅴgroup:ischemic 4h and reperfusion 8h;Ⅵgroup: ischemic 4h and reperfusion 16h;Ⅶgroup:ischemic 4h and reperfusion24h.the first part:to observe pathological change of myocardium by using light microscope,to measure the content of MDA、T-SOD and MPO in the serum and myocardium.;the second part:to detect the expression of HO-1mRNA by using RT-PCR.
Result:After reperfusion 4h,myocardial cells were engorged, Vascular engorgement and Small spatium intermusculares were widen obviously,a bulk of akaryocyte and nucleated cells were observed in the spatium intermusculare,above-mentioned change were lessen following reperfusion 24h.To compare with normal group normal,plasma and myocardium MDA:The levels of MDA,MPO in plasma and the levels of MDA,MPO in myocardium were significantly increased in all groups of IR(P＜0.01),and the myocardial and plasma levels of SOD were markedly decreased(P＜0.01).However,the plasma levels of MDA and MPO and the myocardial level of MDA achieved to high-peak after reperfusion for 4h,then they decreased,while,the myocardial level of MPO reach to high-peak following IR for 6h,the plasma level of SOD reach to nadir after IR for 4h,but the myocardial level of SOD reach to nadir following IR for 8h.limb IR can induce to up-regulation of HO-1mRNA,compared to grounp normal:the expression of HO-1 was not significant change after IR2h(P＞0.05).and it is markedly increased after IR4h,and up to peak after IR16h(P＜0.01).
Conclusion:Limb IR can induce myocardial injury.the injury is the most serious during 4-6h after reperfusion.The mechanism may be involved in the activating of neutrophil and inflammatory cytokines,excess oxidative stress,the imbalance of oxidant-antioxidant system,organism have the mechanism of autoprotection,the up-regulation of endogenous HO-1 may play an important role in myocardial injury following limb IR.
本实验应用止血带构建大鼠下肢缺血再灌注模型,观察肢体缺血再灌注后心肌病理学改变,氧化应激机制及诱导型血红素氧化酶(HO-1)的表达来说明心肌的损伤及自身保护机制。本实验分为两个部分:一,观察肢体缺血再灌注后心肌的损伤变化,并了解氧化应激在肢体缺血再灌注后继发的心肌损伤中的作用。二,观察内源性HO-1在肢体缺血再灌注后心肌中的表达变化的规律及其意义。
方法:本实验应用止血带捆扎大鼠下肢来构造肢体缺血再灌注模型,将实验的大鼠随机分为七组。即:正常组,缺血4小时再灌注2小时组,再灌注4小时组,再灌注6小时组,再灌注8小时组,再灌注16小时组,再灌注24小时组。第一部分实验:应用光镜观察心肌组织的病理变化;分别测定血清及心肌组织中的丙二醛(MDA)含量、总超氧化物歧化酶(T-SOD)活力及髓过氧化物酶(MPO)活性。第二部分实验:应用反转录—多聚酶链反应(RT-PCR)检测心肌HO-1mRNA表达的变化规律。
结果:缺血再灌注4,6小时,心肌细胞明显肿胀,肌间隙增宽,小血管充血明显,肌间隙内可见大量红细胞漏出,肌间隙有核细胞明显增多,再灌注24小时上述改变减轻。与正常组比较,血浆MDA及心肌MDA:缺血再灌注各组均明显升高(P＜0.01),再灌注4h达高峰;血浆SOD:缺血再灌注各组均明显下降(P＜0.01),再灌注4小时达最低值,心肌SOD:再灌注各组均明显下降(P＜0.01),再灌注8小时达最低值;血浆及心肌MPO:缺血再灌注2h～8h出现明显升高(P＜0.01),血浆MPO 4h达高峰,心肌MPO 6h达高峰,16,24h下降。肢体缺血再灌注可诱导HO-1mRNA在心肌表达上调,与正常组比较,再灌注2h,HO-1mRNA表达无显著变化(P＞0.05);再灌注4h,6h,8h,16h,24h后HO-1表达显著增强(P＜0.01),并在16h达高峰。
结论:肢体缺血再灌注可造成心肌损伤,再灌注4-6小时心肌损伤最重,全身及心肌局部的炎细胞聚集活化,炎性因子的激活和过度的氧化应激及氧化抗氧化失衡是肢体缺血再灌注致心肌损伤的机制,机体存在自身保护机制,活性氧族及炎性因子能上调HO-1的表达,对抗氧化应激,从而发挥心肌细胞保护作用。
Objective and background:ischemical reperfusion injury of limb is a common pathophysiological phenomenon clinically.Ischemia of the limbs is a unavoidable occurrence during peripheral vasculai surgery, insult of limbs、thrombogenesis、abdominal aneurysm surgery, replantation of extremities,peripheral vascular injury or crushing syndrome.Recent studies have shown that limb IR can trigger a systemic inflammatory response syndrome(SIRS).It causes not only local tissue injury,but also remote organs dysfunction including heart,liver,lung,kindy and small intestine.clinical studies suggest that the heart is at high risk in the setting of sirs.the mechanism of acute myocardial injury following limb IR is very complicated,up to now,not completely elucidated yet.a great quantity of study indicate that severe ischemical reperfusion injury of limb can induce irritable high blood pressure,arrhythmia,myocardial ischemia and cardia insufficiency,heme oxygenase-1 is a ubiquitous stress protein and is induced in many cell types by various stimuli.the this stimuli all can induce oxidative stress.The protective effects of HO-1 is very important via its antiinflammatory,antiapoptotic,antiproliferative, and antioxidant properties,as well as its effects on the immune response. In the present study,we have established the model of bilateral hindlimb ischemia and reperfusion in rats by using a tourniquet.To explain the mechanism of myocardial injury and autoprotection by observing pathologic change of myocardium,the mechanism of oxidative stress and the expression of HO-1mRNA..our experiment is divided into two parts:Firstly,we explore the role of oxidative stress in the myocardial injury following the limb ischemical reperfusion injury by observing change of myocardium.secondly,we are to ascertain the protective effects of endogenous HO-lon the myocardial injury during the limb ischemical reperfusion.
Method:we have established the model of bilateral hindlimb ischemia and reperfusion in rats by using a tourniquet.the experimental rats were divided to 7 groups randomly.Igroup:Normal group;Ⅱgroup:a group of animals were subjected to suffer ischemic 4h and reperfusion 2h,Ⅲgroup:ischemic 4h and reperfusion 4h;Ⅳgroup:ischemic 4h and reperfusion 6h;Ⅴgroup:ischemic 4h and reperfusion 8h;Ⅵgroup: ischemic 4h and reperfusion 16h;Ⅶgroup:ischemic 4h and reperfusion24h.the first part:to observe pathological change of myocardium by using light microscope,to measure the content of MDA、T-SOD and MPO in the serum and myocardium.;the second part:to detect the expression of HO-1mRNA by using RT-PCR.
Result:After reperfusion 4h,myocardial cells were engorged, Vascular engorgement and Small spatium intermusculares were widen obviously,a bulk of akaryocyte and nucleated cells were observed in the spatium intermusculare,above-mentioned change were lessen following reperfusion 24h.To compare with normal group normal,plasma and myocardium MDA:The levels of MDA,MPO in plasma and the levels of MDA,MPO in myocardium were significantly increased in all groups of IR(P＜0.01),and the myocardial and plasma levels of SOD were markedly decreased(P＜0.01).However,the plasma levels of MDA and MPO and the myocardial level of MDA achieved to high-peak after reperfusion for 4h,then they decreased,while,the myocardial level of MPO reach to high-peak following IR for 6h,the plasma level of SOD reach to nadir after IR for 4h,but the myocardial level of SOD reach to nadir following IR for 8h.limb IR can induce to up-regulation of HO-1mRNA,compared to grounp normal:the expression of HO-1 was not significant change after IR2h(P＞0.05).and it is markedly increased after IR4h,and up to peak after IR16h(P＜0.01).
Conclusion:Limb IR can induce myocardial injury.the injury is the most serious during 4-6h after reperfusion.The mechanism may be involved in the activating of neutrophil and inflammatory cytokines,excess oxidative stress,the imbalance of oxidant-antioxidant system,organism have the mechanism of autoprotection,the up-regulation of endogenous HO-1 may play an important role in myocardial injury following limb IR.
引文
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[11] Otterbein LE, Choi AM. The saga of leucine zippers continues: in response to oxidative stress. Am J Respir Cell Mol Biol. 2002 Feb;26(2):161-3.
[12] Alam J, Camhi S, Choi AM. Identification of a second region upstream of the mouse heme oxygenase-1 gene that functions as a basal level and inducer-dependent transcription enhancer. J Biol Chem. 1995 May 19;270(20):11977-84.
[13] Lee PJ, Camhi SL, Chin BY, ,et al. AP-1 and STAT mediate hyperoxia-induced gene transcription of heme oxygenase-1. Am J Physiol Lung Cell Mol Physiol. 2000 Jul;279(1):L175-82
[14] Rensing H, Jaeschke H, Bauer I, ,et al. Differential activation pattern of redox-sensitive transcription factors and stress-inducible dilator systems heme oxygenase-1 and inducible nitric oxide synthase in hemorrhagic and endotoxic shock. Crit Care Med. 2001 Oct;29(10):1962-71
[15] Chin BY, Jiang G, Wegiel B, ,et al. Hypoxia-inducible factor lalpha stabilization by carbon monoxide results in cytoprotective preconditioning. Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5109-14. Epub 2007 Mar 12
[16] Yang ZZ, Zhang AY, Yi FX. Redox regulation of HIF-lalpha levels and HO-1 expression in renal medullary interstitial cells. Am J Physiol Renal Physiol. 2003 Jun;284(6):F1207-15. Epub 2003 Feb 20.
[17] Alam J, Wicks C, Stewart D, ,et al. Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells. Role of p38 kinase and Nrf2 transcription factor. J Biol Chem. 2000 Sep 8;275(36):27694-702
[18] Tanaka Y, Maher JM, Chen C, ,et al. Hepatic ischemia-reperfusion induces renal heme oxygenase-1 via NF-E2-related factor 2 in rats and mice. Mol Pharmacol. 2007 Mar;71(3):817-25. Epub 2006 Dec 6.
[19] Yano Y, Ozono R, Oishi Y, ,et al. Genetic ablation of the transcription repressor Bachl leads to myocardial protection against ischemia/reperfusion in mice.Genes Cells. 2006 Jul;11(7):791-803.
[20] Masuya Y, Hioki K, Tokunaga R,et al. Involvement of the tyrosine phosphorylation pathway in induction of human heme oxygenase-1 by hemin, sodium arsenite, and cadmium chloride. J Biochem. 1998 Sep;124(3):628-33
[21] Elbirt KK, Bonkovsky HL. Heme oxygenase: recent advances in understanding its regulation and role. Proc Assoc Am Physicians. 1999 Sep-Oct;111(5):438-47.
[22] Sethi JM, Otterbein LE, Choi AM. Differential modulation by exogenous carbon monoxide of TNF-alpha stimulated mitogen-activated protein kinases in rat pulmonary artery endothelial cells. Antioxid Redox Signal. 2002 Apr;4(2):241-8.
[23] Chen K, Gunter K, Maines MD. Neurons overexpressing heme oxygenase-1resist oxidative stress-mediated cell deathJ Neurochem. 2000 Jul;75(1):304-13.
[26] Pedraza-Chaverri J, Murali NS, Croatt AJ, Proteinuria as a determinant of renal expression of heme oxygenase-1: studies in models of glomerular and tubular proteinuria in the rat. Am J Physiol Renal Physiol. 2006 Jan;290(1):F196-204.Epub 2005 Aug 23
[27] Gueler F, Park JK, Rong S, Statins attenuate ischemia-reperfusion injury by inducing heme oxygenase-1 in infiltrating macrophages. Am J Pathol. 2007 Apr;170(4):1192-9.
[28] Pachori AS, Smith A, McDonald P at.Heme-oxygenase-1 -induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway. Mol Cell Cardiol. 2007 Nov;43(5):580-92. Epub 2007 Aug 17.
[29] Zu Vilsendorf AM, Terbish T Induction of heme oxygenase-1 improves the survival of pancreas grafts by prevention of pancreatitis after transplantation. Transplantation. 2007 Dec 27;84(12):1644-55.
[30] Ferris CD, Jaffrey SR, Sawa A, Hame oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol. 1999 Jul;1(3): 152-7.
[31] Petrache I, Otterbein LE, Alam J, Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2000 Feb;278(2):L312-9
[32] Liu SH, Xu XR, Ma K, Protection of carbon monoxide inhalation on lipopolysaccharide-induced multiple organ injury in rats. Chin Med Sci J. 2007 Sep;22(3): 169-76.
[33] Brouard S, Otterbein LE, Anrather J,et al. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis J Exp Med. 2000 Oct 2; 192(7): 1015-26.
[34] Stone JR, Marietta MA. Heme stoichiometry of heterodimeric soluble guanylate cyclase. Biochemistry. 1995 Nov 14;34(45): 14668-74.
[35] Martin E, Berka V, Bogatenkova E,et al. Ligand selectivity of soluble guanylyl cyclase: effect of the hydrogen-bonding tyrosine in the distal heme pocket on binding of oxygen, nitric oxide, and carbon monoxide. J Biol Chem. 2006 Sep 22;281(38):27836-45. Epub 2006 Jul 24.
[36] Bak I, Szendrei L. Turoczi T,et al. Heme oxygenase-1-related carbon monoxide production and ventricular fibrillation in isolated ischemic/reperf'used mouse myocardium. FASEB J. 2003 Nov;17(14):2133-5. Epub 2003 Sep 4.
[37] Benallaoua M, Frangois M, Batteux F, et al.Pharmacologic induction of heme oxygenase 1 reduces acute inflammatory arthritis in mice. Arthritis Rheum. 2007 Aug;56(8):2585-94.
[38] Otterbein LE, Kolls JK, Mantell LL,et al. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J Clin Invest. 1999 Apr;103(7):1047-54
[39] Otterbein LE, Mantell LL, Choi AM. Carbon monoxide provides protection against hyperoxic lung injury. Am J Physiol. 1999 Apr;276(4 Pt 1):L688-94.
[40] Clayton CE, Carraway MS, Suliman HB,et al. Inhaled carbon monoxide and hyperoxic lung injury in rats. Am J Physiol Lung Cell Mol Physiol. 2001 Oct;281(4):L949-57.
[41] Inoue S, Suzuki M, Nagashima Y,et al. Transfer of heme oxygenase 1 cDNA by a replication-deficient adenovirus enhances interleukin 10 production from alveolar macrophages that attenuates lipopolysaccharide-induced acute lung injury in mice. Hum Gene Ther. 2001 May 20;12(8):967-79.
[42] Wang X, Wang Y, Kim HP,et al. Carbon monoxide protects against hyperoxia-induced endothelial cell apoptosis by inhibiting reactive oxygen species formation. J Biol Chem. 2007 Jan 19;282(3):1718-26. Epub 2006 Nov 29.
[43] Harju T, Soini Y, Paakko R, Up-regulation of heme oxygenase-I in alveolar macrophages of newly diagnosed asthmatics. Respir Med. 2002 Jun;96(6):418-23
[44] McFaul SJ, McGrath JJ. Studies on the mechanism of carbon monoxide-induced vasodilation in the isolated perfused rat heart. Toxicol Appl Pharmacol. 1987 Mar 15;87(3):464-73.
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[46] Das S, Fraga CG, Das DK. Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB. Free Radic Res. 2006 Oct;40( 10): 1066-75.
[47] Clark JE, Foresti R, Sarathchandra P, Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction. Am J Physiol Heart Circ Physiol. 2000 Feb;278(2):H643-51.
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[49] Sato K, Balla J, Otterbein L, Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants.J Immunol. 2001 Mar 15;166(6):4185-94.
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[1]Bak I,Szendrei L,Turoczi T,Heme oxygenase-l-related carbon monoxide production and ventricular fibrillation in isolated ischemic/reperfused mouse myocardium.FASEB J.2003 Nov;17(14):2133-5.Epub 2003 Sep 4.
[2]Stocker R..Induction of haem oxygenase as a defence against oxidative stress.Free Radic Res Commun.1990;9(2):101-12.
[3]Yachie A,Niida Y,Wada T,et al.Oxidative stress causes enhanced endothelial cell injury in human heine oxygenase-1 deficiency.J Clin Invest.1999 Jan;103(1):129-35
[4] Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20): 10919-24.
[5] Otterbein LE, Choi AM. Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol. 2000 Dec; 279(6):L1029-37.
[6] Xue H, Guo H, Li YC,et al. Heme oxygenase-1 induction by hemin protects liver cells from ischemia/reperfusion injury in cirrhotic rats. World J Gastroenterol.2007 Oct 28;13(40):5384-90.
[7] Ryter SW, Kim HP, Hoetzel A, Mechanisms of cell death in oxidative stress. Antioxid Redox Signal. 2007 Jan;9(1):49-89.
[8] Okinaga S, Takahashi K, Takeda K,et al. Regulation of human heme oxygenase-1 gene expression under thermal stress.Blood. 1996 Jun 15;87(12):5074-84.
[9] Choi AM, Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 1996 Jul;15(1):9-19
[10] Hill-Kapturczak N, Thamilselvan V, Liu F,et al. Mechanism of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule cells. Am J Physiol Renal Physiol. 2001 Nov;281(5):F851-9.
[11] Otterbein LE, Choi AM. The saga of leucine zippers continues: in response to oxidative stress. Am J Respir Cell Mol Biol. 2002 Feb;26(2):161-3.
[12] Alam J, Camhi S, Choi AM. Identification of a second region upstream of the mouse heme oxygenase-1 gene that functions as a basal level and inducer-dependent transcription enhancer. J Biol Chem. 1995 May 19;270(20):11977-84.
[13] Lee PJ, Camhi SL, Chin BY, ,et al. AP-1 and STAT mediate hyperoxia-induced gene transcription of heme oxygenase-1. Am J Physiol Lung Cell Mol Physiol. 2000 Jul;279(1):L175-82
[14] Rensing H, Jaeschke H, Bauer I, ,et al. Differential activation pattern of redox-sensitive transcription factors and stress-inducible dilator systems heme oxygenase-1 and inducible nitric oxide synthase in hemorrhagic and endotoxic shock. Crit Care Med. 2001 Oct;29(10):1962-71
[15] Chin BY, Jiang G, Wegiel B, ,et al. Hypoxia-inducible factor lalpha stabilization by carbon monoxide results in cytoprotective preconditioning. Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5109-14. Epub 2007 Mar 12
[16] Yang ZZ, Zhang AY, Yi FX. Redox regulation of HIF-lalpha levels and HO-1 expression in renal medullary interstitial cells. Am J Physiol Renal Physiol. 2003 Jun;284(6):F1207-15. Epub 2003 Feb 20.
[17] Alam J, Wicks C, Stewart D, ,et al. Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells. Role of p38 kinase and Nrf2 transcription factor. J Biol Chem. 2000 Sep 8;275(36):27694-702
[18] Tanaka Y, Maher JM, Chen C, ,et al. Hepatic ischemia-reperfusion induces renal heme oxygenase-1 via NF-E2-related factor 2 in rats and mice. Mol Pharmacol. 2007 Mar;71(3):817-25. Epub 2006 Dec 6.
[19] Yano Y, Ozono R, Oishi Y, ,et al. Genetic ablation of the transcription repressor Bachl leads to myocardial protection against ischemia/reperfusion in mice.Genes Cells. 2006 Jul;11(7):791-803.
[20] Masuya Y, Hioki K, Tokunaga R,et al. Involvement of the tyrosine phosphorylation pathway in induction of human heme oxygenase-1 by hemin, sodium arsenite, and cadmium chloride. J Biochem. 1998 Sep;124(3):628-33
[21] Elbirt KK, Bonkovsky HL. Heme oxygenase: recent advances in understanding its regulation and role. Proc Assoc Am Physicians. 1999 Sep-Oct;111(5):438-47.
[22] Sethi JM, Otterbein LE, Choi AM. Differential modulation by exogenous carbon monoxide of TNF-alpha stimulated mitogen-activated protein kinases in rat pulmonary artery endothelial cells. Antioxid Redox Signal. 2002 Apr;4(2):241-8.
[23] Chen K, Gunter K, Maines MD. Neurons overexpressing heme oxygenase-1resist oxidative stress-mediated cell deathJ Neurochem. 2000 Jul;75(1):304-13.
[26] Pedraza-Chaverri J, Murali NS, Croatt AJ, Proteinuria as a determinant of renal expression of heme oxygenase-1: studies in models of glomerular and tubular proteinuria in the rat. Am J Physiol Renal Physiol. 2006 Jan;290(1):F196-204.Epub 2005 Aug 23
[27] Gueler F, Park JK, Rong S, Statins attenuate ischemia-reperfusion injury by inducing heme oxygenase-1 in infiltrating macrophages. Am J Pathol. 2007 Apr;170(4):1192-9.
[28] Pachori AS, Smith A, McDonald P at.Heme-oxygenase-1 -induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway. Mol Cell Cardiol. 2007 Nov;43(5):580-92. Epub 2007 Aug 17.
[29] Zu Vilsendorf AM, Terbish T Induction of heme oxygenase-1 improves the survival of pancreas grafts by prevention of pancreatitis after transplantation. Transplantation. 2007 Dec 27;84(12):1644-55.
[30] Ferris CD, Jaffrey SR, Sawa A, Hame oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol. 1999 Jul;1(3): 152-7.
[31] Petrache I, Otterbein LE, Alam J, Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2000 Feb;278(2):L312-9
[32] Liu SH, Xu XR, Ma K, Protection of carbon monoxide inhalation on lipopolysaccharide-induced multiple organ injury in rats. Chin Med Sci J. 2007 Sep;22(3): 169-76.
[33] Brouard S, Otterbein LE, Anrather J,et al. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis J Exp Med. 2000 Oct 2; 192(7): 1015-26.
[34] Stone JR, Marietta MA. Heme stoichiometry of heterodimeric soluble guanylate cyclase. Biochemistry. 1995 Nov 14;34(45): 14668-74.
[35] Martin E, Berka V, Bogatenkova E,et al. Ligand selectivity of soluble guanylyl cyclase: effect of the hydrogen-bonding tyrosine in the distal heme pocket on binding of oxygen, nitric oxide, and carbon monoxide. J Biol Chem. 2006 Sep 22;281(38):27836-45. Epub 2006 Jul 24.
[36] Bak I, Szendrei L. Turoczi T,et al. Heme oxygenase-1-related carbon monoxide production and ventricular fibrillation in isolated ischemic/reperf'used mouse myocardium. FASEB J. 2003 Nov;17(14):2133-5. Epub 2003 Sep 4.
[37] Benallaoua M, Frangois M, Batteux F, et al.Pharmacologic induction of heme oxygenase 1 reduces acute inflammatory arthritis in mice. Arthritis Rheum. 2007 Aug;56(8):2585-94.
[38] Otterbein LE, Kolls JK, Mantell LL,et al. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J Clin Invest. 1999 Apr;103(7):1047-54
[39] Otterbein LE, Mantell LL, Choi AM. Carbon monoxide provides protection against hyperoxic lung injury. Am J Physiol. 1999 Apr;276(4 Pt 1):L688-94.
[40] Clayton CE, Carraway MS, Suliman HB,et al. Inhaled carbon monoxide and hyperoxic lung injury in rats. Am J Physiol Lung Cell Mol Physiol. 2001 Oct;281(4):L949-57.
[41] Inoue S, Suzuki M, Nagashima Y,et al. Transfer of heme oxygenase 1 cDNA by a replication-deficient adenovirus enhances interleukin 10 production from alveolar macrophages that attenuates lipopolysaccharide-induced acute lung injury in mice. Hum Gene Ther. 2001 May 20;12(8):967-79.
[42] Wang X, Wang Y, Kim HP,et al. Carbon monoxide protects against hyperoxia-induced endothelial cell apoptosis by inhibiting reactive oxygen species formation. J Biol Chem. 2007 Jan 19;282(3):1718-26. Epub 2006 Nov 29.
[43] Harju T, Soini Y, Paakko R, Up-regulation of heme oxygenase-I in alveolar macrophages of newly diagnosed asthmatics. Respir Med. 2002 Jun;96(6):418-23
[44] McFaul SJ, McGrath JJ. Studies on the mechanism of carbon monoxide-induced vasodilation in the isolated perfused rat heart. Toxicol Appl Pharmacol. 1987 Mar 15;87(3):464-73.
[45] Kourembanas S, Morita T, Liu Y, Mechanisms by which oxygen regulates gene expression and cell-cell interaction in the vasculature. Kidney Int. 1997 Feb;51(2):438-43.
[46] Das S, Fraga CG, Das DK. Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB. Free Radic Res. 2006 Oct;40( 10): 1066-75.
[47] Clark JE, Foresti R, Sarathchandra P, Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction. Am J Physiol Heart Circ Physiol. 2000 Feb;278(2):H643-51.
[48] Musameh MD, Fuller BJ, Mann BE, Positive inotropic effects of carbon monoxide-releasing molecules (CO-RMs) in the isolated perfused rat heart. Br J Pharmacol. 2006 Dec;149(8):1104-12. Epub 2006 Oct 23.
[49] Sato K, Balla J, Otterbein L, Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants.J Immunol. 2001 Mar 15;166(6):4185-94.