血红素氧合酶-1 在脑损伤过程中的作用的研究进展

来源于出血后血红蛋白或衰老细胞释放的血红素能够诱导血红素氧合酶-1(HO-1,HSP-1)的表达。血红素氧合酶-1催化血红素生成气体介质一氧化碳,铁和胆绿素。胆绿素和它的代谢产物胆红素都是有效的抗氧化剂;同时铁诱导的铁蛋白和CO也发挥着各自的保护作用。因此,HO-1的表达被看作一种重要的保护机制。在各种不同的脑病理改变发生后,如蛛网膜下腔出血,脑梗死,创伤性脑损伤及神经变性疾病,HO-1明显表达于小胶质细胞,星形细胞和神经元细胞,从而发挥其重要脑保护作用。     

血红素加氧酶-1在消化系统疾病中的作用

血红素加氧酶-1(heme oxygenase-1,HO-1)是血红素分解代谢过程中的限速酶。HO-1及其降解产物(CO、胆绿素及Fe~(2+))能够通过各种途径调节机体免疫功能、抑制炎症反应和细胞凋亡,在消化系统疾病中发挥潜在的保护作用。该文综述了HO-1基因的表达和调节及其在胃肠道和肝病中的作用。     

脑血红素加氧酶系统的作用研究

血红素加氧酶（HO）是降解血红素的微粒体酶系统,催化降解血红素生成一氧化碳（CO）、胆绿素和铁离子,同工酶HO-1和HO-2广泛分布于脑中,具有不同的调控机制,可能发挥着调节NO水平,抗氧化应激,参与神经元退行性变等重要作用。     

血红素氧合酶与动脉粥样硬化

血红素氧合酶(HO)通过降解血红素产生一氧化碳(CO)、胆绿素和铁离子。CO是继一氧化氮(NO)之后发现的另一种具有重要生理作用的气体分子,具有调节血管张力、抑制血管平滑肌细胞增殖、抑制血小板聚集等效应;胆绿素和铁蛋白具有抗氧化和细胞保护作用。具有可诱导性的HO-1在心血管疾病尤其是在动脉粥样硬化及血管成形术后再狭窄中有重要的病理生理意义。HO-1的调控可能成为动脉粥样硬化防治的新手段。     

UVA照射通过诱导HO-1的表达对细胞产生保护作用

长波紫外线A(UVA,320～400nm)照射皮肤后可产生活性氧族(reactive oxygen species,ROS),导致细胞损伤或免疫抑制,还能增强UVB的损伤作用。但也有研究表明,UVA照射不会产生免疫抑制,它可通过诱导血红素氧合酶1(HO-1)的表达减轻UVB照射引起的免疫抑制效应,从而对细胞产生保护作用。由于UVA照射引起的损伤或保护作用尚存在很大争议,本文主要结合近年来的相关研究,概括了适量UVA照射引起的免疫改变以及相关研究,总结了UVA照射诱导HO-1表达所发挥的细胞保护作用,尤其是HO-1的抗氧化和免疫保护作用,这将为深入了解UVA照射的反应机制和新型防晒剂的应用提供一定的指导意义。     

血红素氧合酶-1与肺纤维化

血红素氧合酶-1（Hene Oxygenase-1）是一种氧化应激反应蛋白,广泛存在全身各组织器官。HO-1及催化产物组成了重要的内源性保护系统,具有调控炎症、抗氧化损伤及抗细胞凋亡等作用,对于组织器官具有保护作用。肺纤维化发病机制复杂,氧化应激是肺纤维化的致病机制之一。HO-1是一种重要的抗氧化剂,其通过多种途径参与致病,在肺纤维化致病过程中发挥重要作用。     

血红素氧合酶-1 与肺纤维化

血红素氧合酶-1(Hene Oxygenase-1)是一种氧化应激反应蛋白,广泛存在全身各组织器官。HO-1及催化产物组成了重要的内源性保护系统,具有调控炎症、抗氧化损伤及抗细胞凋亡等作用,对于组织器官具有保护作用。肺纤维化发病机制复杂,氧化应激是肺纤维化的致病机制之一。HO-1是一种重要的抗氧化剂,其通过多种途径参与致病,在肺纤维化致病过程中发挥重要作用。     

血红素氧合酶-1对肝癌作用的研究进展

血红素氧合酶-1(heme oxygenase,HO-1)是细胞内的一种可诱导的保护性酶,具有抗氧化、抗炎、抗凋亡等作用。它在肿瘤细胞(如肝癌细胞)中的表达一般会增强,能影响肿瘤细胞的增殖等生物学行为。一方面,HO-1能促进肝癌细胞的生长和扩散,并通过减少氧化应激产生的氧自由基而对肝癌细胞发挥保护作用,使肝癌细胞对治疗产生抵抗性。另一方面,HO-1使肝移植治疗晚期肝癌中的免疫排斥降低,提高肝移植的成功率。本文简要概括了HO-1对肝癌发生进展的影响,并阐述了HO-1在肝移植方面的重要作用,这可能对抗肝癌药物的研发及肝癌的治疗具有一定的指导意义。     

实验性变态反应性脑脊髓炎大鼠发病中脑组织血红素氧合酶-1基因和蛋白表达的动态变化

为探讨脑组织血红素氧合酶-1(hemeoxygenase-1,HO-1)对实验性变态反应性脑脊髓炎(experimental allergic encephalomyelitis,EAE)的作用,分别应用逆转录-聚合酶链反应(RT-PCR)和免疫组化技术测定了豚鼠脊髓生理盐水匀浆 完全福氏佐剂诱导EAE大鼠1、7、14、21d时,脑组织HO-1基因和蛋白表达的动态变化,并观察与症状之间的关系。结果显示：对照组大鼠脑组织仅有少量HO-1基因和蛋白表达：诱导EAE后,伴随着大鼠EAE症状及脑组织病理损伤的出现和进行性加重,脑组织HO-1基因和蛋白表达量逐渐增高。在豚鼠脊髓生理盐水匀浆 完全福氏佐剂诱导7d后,HO-1 mRNA上升至高峰。14d时,HO-1蛋白表达至高峰,HO-1阳性细胞主要位于脉络丛、穹隆下器、血管“套袖样”病灶的周围,与EAE病变部位一致。此时大鼠的病情最重、体重减轻最显著、脑组织病理改变最明显。21d时脑组织HO-1基因和蛋白表达量逐渐下降,大鼠EAE症状也逐渐减轻。应用HO-1特异性抑制剂锡原卟啉-9以抑制脑内HO-1蛋白表达后,大鼠EAE症状和脑组织损伤明显减轻,说明脑组织HO-1的动态变化与EAE症状及脑组织损伤密切相关。提示脑组织HO-1基因和蛋白过表达对EAE发病起着重要的作用,应用HO-1抑制剂可能是防治该病的有效方法之一。     

高浓度葡萄糖下调INS-1细胞血红素氧合酶1表达水平的研究

目的:观察高糖毒性对大鼠胰岛细胞系INS-1细胞中血红素氧合酶1蛋白表达的损害作用,并研究信号分子刺激下细胞损伤的自我保护机制.方法:分别采用不同葡萄糖浓度孵育或葡萄糖代谢物葡萄糖胺持续孵育培养INS-1细胞,造成高糖毒性损伤,进而采用胰岛素以及核转录因子Nrf2激动剂莱芜硫烷刺激细胞保护信号机制改善损伤,蛋白印迹法检测细胞中血红素氧合酶1的表达情况.结果:高浓度葡萄糖溶液中(25 mM)孵育INS-1细胞48小时,血红素氧合酶1的表达水平较正常情况显著下降(P＜0.05).高浓度葡萄糖与葡萄糖胺共刺激对实验细胞中血红素氧合酶1的表达下调具有协同作用.胰岛素对实验细胞中血红素氧合酶1表达具有上调作用,但上调作用强度随培养环境中葡萄糖浓度的增高而降低.核转录因子Nrf2激动剂莱芜硫烷孵育处理实验细胞后,胞内血红素氧合酶1表达水平在葡萄糖胺刺激下上调,且与培养环境中葡萄糖浓度水平无关(P＜0.05).结论:高糖毒性可损害胰岛β细胞内抗氧化酶-血红素氧合酶Ⅰ的表达,而胰岛素可激活下游通路尤其是Nrf2信号通路,对抗高糖诱导的氧化应激损伤,从而保护胰岛细胞.     

Modulation of heme oxygenase in tissue injury and its implication in protection against gastrointestinal diseases.

Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme, followed by production of biliverdin, free iron and carbon monoxide (CO). There are three isoforms of HO: HO-1 is highly inducible, whereas HO-2 and HO-3 are constitutively expressed. In addition to heme, a variety of nonheme compounds, including heavy metals, cytokines, endotoxins and heat shock stress are strong inducers of HO-1 expression. Many studies indicated that induction of HO-1 is associated with a protective response due to the removal of free heme, which is shown to be toxic. However, recent studies demonstrated that the expression of HO-1 in response to different inflammatory mediators could contribute in part to the resolution of inflammation and have protective effects on brain, liver, kidney and lung against injuries. These beneficial effects seem to be due to the production of bile pigment biliverdin and bilirubin that is a potent antioxidant, as well as the release of iron and CO. However, there are few studies concerning the relationship between HO-1 and inflammation as well as injury in the gut. Interestingly, a preliminary study implicated that induction of HO-1 expression in a colonic damage model induced by trinitrobenzene sulfonic acid played a critical protective role, indicating that activation of HO-1 could act as a natural defensive mechanism to alleviate inflammation and tissue injury in the gastrointestinal tract.     

Heme oxygenase-1 (HO-1), a protective gene that prevents chronic graft dysfunction

Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that acts during inflammatory reactions as the rate-limiting step in the catabolism of heme, yielding equimolar amounts of iron (Fe), biliverdin, and the gas carbon monoxide (CO). Expression of HO-1 regulates inflammatory and immune responses, such as those involved in the rejection of transplanted organs. We will discuss here accumulating evidence supporting the notion that expression of HO-1 in a transplanted organ can prevent its rejection. We will argue that the protective effects exerted by HO-1 are mediated to a large extent by the end products that it generates via the catabolism of heme. Better knowledge of how to enhance these protective effects is likely to help create new therapeutic strategies to improve the outcome of transplanted organs.     

血红素加氧酶介导GA对小麦糊粉层中α-淀粉酶的诱导表达

单独以赤霉素（GA）处理或与HO．1诱导物高铁血红素（Ht）和CO水溶液组合处理均导致小麦糊粉层中血红素加氧酶（H0）活性的提高,同时仪-淀粉酶基因表达和α-淀粉酶活性也明显受诱导;用HO-1专一性抑制剂锌原卟啉（ZnPPIX）预处理6h后,上述效应部分受阻断。这暗示HO可能参与GA诱导的α-淀粉酶基因表达。     

Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement

The heme oxygenases (HOs), responsible for the degradation of heme to biliverdin/bilirubin, free iron and CO, have been heavily implicated in mammalian CNS aging and disease. In normal brain, the expression of HO-2 is constitutive, abundant and fairly ubiquitous, whereas HO-1 mRNA and protein are confined to small populations of scattered neurons and neuroglia. In contradistinction to HO-2, the ho-1 gene ( Hmox1 ) is exquisitely sensitive to induction by a wide range of pro-oxidant and other stressors. In Alzheimer disease and mild cognitive impairment, immunoreactive HO-1 protein is over-expressed in neurons and astrocytes of the cerebral cortex and hippocampus relative to age-matched, cognitively intact controls and co-localizes to senile plaques, neurofibrillary tangles, and corpora amylacea. In Parkinson disease, HO-1 is markedly over-expressed in astrocytes of the substantia nigra and decorates Lewy bodies in affected dopaminergic neurons. HMOX1 is also up-regulated in glial cells surrounding human cerebral infarcts, hemorrhages and contusions, within multiple sclerosis plaques, and in other degenerative and inflammatory human CNS disorders. Heme-derived free ferrous iron, CO, and biliverdin/bilirubin are biologically active substances that have been shown to either ameliorate or exacerbate neural injury contingent upon specific disease models employed, the intensity and duration of HO-1 expression and the nature of the prevailing redox microenvironment. In 'stressed' astroglia, HO-1 hyperactivity promotes mitochondrial sequestration of non-transferrin iron and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure amply documented in Alzheimer disease, Parkinson disease and other aging-related neurodegenerative disorders. Glial HO-1 expression may also impact cell survival and neuroplasticity in these conditions by modulating brain sterol metabolism and proteosomal degradation of neurotoxic protein aggregates.     

Carbon monoxide as an endogenous vascular modulator

Carbon monoxide (CO) is produced by heme oxygenase (HO)-catalyzed heme degradation to CO, iron, and biliverdin. HO has two active isoforms, HO-1 (inducible) and HO-2 (constitutive). HO-2, but not HO-1, is highly expressed in endothelial and smooth muscle cells and in adjacent astrocytes in the brain. HO-1 is expressed basally only in the spleen and liver but can be induced to a varying extent in most tissues. Elevating heme, protein phosphorylation, Ca(2+) influx, and Ca(2+)/calmodulin-dependent processes increase HO-2 activity. CO dilates cerebral arterioles and may constrict or dilate skeletal muscle and renal arterioles. Selected vasodilatory stimuli, including seizures, glutamatergic stimulation, hypoxia, hypotension, and ADP, increase CO, and the inhibition of HO attenuates the dilation to these stimuli. Astrocytic HO-2-derived CO causes glutamatergic dilation of pial arterioles. CO dilates by activating smooth muscle cell large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels. CO binds to BK(Ca) channel-bound heme, leading to an increase in Ca(2+) sparks-to-BK(Ca) channel coupling. Also, CO may bind directly to the BK(Ca) channel at several locations. Endothelial nitric oxide and prostacyclin interact with HO/CO in circulatory regulation. In cerebral arterioles in vivo, in contrast to dilation to acute CO, a prolonged exposure of cerebral arterioles to elevated CO produces progressive constriction by inhibiting nitric oxide synthase. The HO/CO system is highly protective to the vasculature. CO suppresses apoptosis and inhibits components of endogenous oxidant-generating pathways. Bilirubin is a potent reactive oxygen species scavenger. Still many questions remain about the physiology and biochemistry of HO/CO in the circulatory system and about the function and dysfunction of this gaseous mediator system.     

Pentoxifylline protects L929 fibroblasts from TNF-alpha toxicity via the induction of heme oxygenase-1

Tumor necrosis factor-alpha (TNF-alpha) is recognized as a principal mediator of a variety of inflammatory conditions. Pentoxifylline (PTX), which can inhibit cellular TNF-alpha synthesis, also attenuates the toxic effect of TNF-alpha. However, the mechanism underlying PTX-induced cytoprotection is unknown. Heme oxygenase 1 (HO-1) is an enzyme which degrades heme into biliverdin, free iron, and carbon monoxide (CO). This enzyme has recently been shown to have anti-inflammatory and cytoprotective effects. In this study, we investigated whether protection by PTX against TNF-alpha-mediated toxicity could be related to its ability to induce HO-1 expression and HO activity in L929 cells. PTX in the range of 0.1-1.0mM significantly induced HO-1 expression and the resulting HO activity. Pre-incubation of L929 cells with either PTX or the HO activator hemin resulted in the protection of the cells against TNF-alpha-mediated toxicity. Zinc protoporphyrin, a specific HO competitive inhibitor, abrogated the protective effect of PTX. Hemoglobin, a scavenger of CO, reversed the protective effect of PTX. A cytoprotection comparable to PTX was observed when the cells were treated with the CO-releasing compound tricarbonyldichlororuthenium(II) dimer. These results suggest that HO-1 expression and the ensuing formation of the HO metabolite CO may be a novel pathway by which PTX protects L929 cells from TNF-alpha-mediated toxicity.     

Impact of heme oxygenase-1 on cholesterol synthesis, cholesterol efflux and oxysterol formation in cultured astroglia

Up-regulation of heme oxygenase-1 (HO-1) and altered cholesterol (CH) metabolism are characteristic of Alzheimer-diseased neural tissues. The liver X receptor (LXR) is a molecular sensor of CH homeostasis. In the current study, we determined the effects of HO-1 over-expression and its byproducts iron (Fe²⁺), carbon monoxide (CO) and bilirubin on CH biosynthesis, CH efflux and oxysterol formation in cultured astroglia. HO-1/LXR interactions were also investigated in the context of CH efflux. hHO-1 over-expression for 3 days (∼2–3-fold increase) resulted in a 30% increase in CH biosynthesis and a two-fold rise in CH efflux. Both effects were abrogated by the competitive HO inhibitor, tin mesoporphyrin. CO, released from administered CORM-3, significantly enhanced CH biosynthesis; a combination of CO and iron stimulated CH efflux. Free iron increased oxysterol formation three-fold. Co-treatment with LXR antagonists implicated LXR activation in the modulation of CH homeostasis by heme degradation products. In Alzheimer's disease and other neuropathological states, glial HO-1 induction may transduce ambient noxious stimuli (e.g. β-amyloid) into altered patterns of glial CH homeostasis. As the latter may impact synaptic plasticity and neuronal repair, modulation of glial HO-1 expression (by pharmacological or other means) may confer neuroprotection in patients with degenerative brain disorders.     

诱导血红素加氧酶-1表达在器官移植中的保护作用

器官移植术中及术后移植器官的缺血再灌注损伤（ischemia-repeffusion injury,IRI）和免疫排斥反应一直困扰着外科医生.血红素加氧酶-1（heme oxygenase-1,HO-1）是血红素代谢过程中的限速酶,广泛分布于哺乳动物的各种组织细胞中.血红素在它的催化下降解代谢为一氧化碳（CO）、胆绿素和游离铁离子.HO-1在氧化应激、炎性反应、低氧和缺血等状态下均能高度表达.HO-1及其催化血红素代谢产物主要通过抗炎性反应、抗氧化反应、调节同种异体反应性T细胞的活性及增殖、抗内皮细胞凋亡、抑制内皮细胞活化等作用机制,对移植器官起到抗IRI和抗免疫排斥作用,从而增加移植器官成活率及延长其存活时间.