Heme Oxygenase-1 and Carbon Monoxide in the Heart

Otterbein, Leo E.; Foresti, Roberta; Motterlini, Roberto

doi:10.1161/circresaha.116.306588

Cited by 170 publications

(95 citation statements)

References 221 publications

(252 reference statements)

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“…As above, HMOX1 is induced following paraquat exposure. HMOX1/HO-1 is an inducible isoform of heme oxygenase and a prominent NRF2-dependent factor in oxidative stress response both in the heart and in other tissues under general oxidative stress conditions [23]. HMOX1 degrades heme into iron, CO, and biliverdin, the latter being an antioxidant that scavenges peroxyl radicals [24].…”

Section: Resultsmentioning

confidence: 99%

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

Dostal

Wood

Thomas

et al. 2020

Preprint

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The heart is sensitive to oxidative damage but a global view on how the cardiac proteome responds to oxidative stressors has yet to fully emerge. Using quantitative tandem mass spectrometry, we assessed the effects of acute exposure of the oxidative stress inducer paraquat on protein expression in mouse hearts. We observed widespread protein expression changes in the paraquat-exposed heart especially in organelle-containing subcellular fractions. During cardiac response to acute oxidative stress, proteome changes are consistent with a rapid reduction of mitochondrial metabolism, coupled with activation of multiple antioxidant proteins, reduction of protein synthesis and remediation of proteostasis. In addition to differential expression, we saw evidence of spatial reorganizations of the cardiac proteome including the translocation of hexokinase 2 to more soluble fractions. Treatment with the antioxidants Tempol and MitoTEMPO reversed many proteomic signatures of paraquat but this reversal was incomplete. We also identified a number of proteins with unknown function in the heart to be triggered by paraquat, suggesting they may have functions in oxidative stress response. Surprisingly, protein expression changes in the heart correlate poorly with those in the lung, consistent with differential sensitivity or stress response in these two organs. The results provide insights into oxidative stress responses in the heart and may avail the search for new therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

Dostal

Wood

Thomas

et al. 2020

Preprint

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“…HO-catalyzed heme breakdown in astrocytes yields iron, which is sequestered (Hoepken et al, 2004), bilirubin, which is exported via multidrug resistance protein 1 (Gennuso et al, 2004), and CO, which is freely diffusible. The latter two products have antioxidant, anti-inflammatory, and vasodilatory effects that combined with heme elimination likely contribute to the neuroprotection observed in GFAP.HMOX1 mice (Leffler et al, 2011; Otterbein et al, 2016; Stocker et al, 1987). …”

Section: Discussionmentioning

confidence: 99%

Astrocyte heme oxygenase-1 reduces mortality and improves outcome after collagenase-induced intracerebral hemorrhage

Chen-Roetling

Kamalapathy

Cao

et al. 2017

Neurobiology of Disease

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Pharmacotherapies that increase CNS expression of heme oxygenase-1 (HO-1) and other antioxidant proteins have improved outcome in experimental models of spontaneous intracerebral hemorrhage (ICH). In order to more specifically investigate the relationship between HO-1 and ICH outcome, mice expressing human HO-1 driven by the glial fibrillary acidic protein (GFAP) promoter (GFAP.HMOX1 mice) were tested in a model of in situ parenchymal hemorrhage. Injection of collagenase into the striata of wild-type (WT) mice resulted in a 26.3% mortality rate, with deaths equally distributed between males and females. Mortality was reduced to 4.48% in GFAP.HMOX1 mice. Cell viability in the injected striata of surviving WT mice was reduced by about half at one week and was significantly increased in transgenics; this benefit persisted over a 22 day observation period. Cell counts guided by design-based stereology indicated loss of ~40% of neurons in WT hemorrhagic striata at one week, which was decreased by half in transgenics; no significant differences in microglia or astrocyte numbers were observed. Blood-brain barrier disruption and short-term neurological deficits were also mitigated in GFAP.HMOX1 mice, but long-term outcome did not differ from that of WT survivors. These results suggest that astrocyte HO-1 overexpression provides robust neuroprotection after acute intracerebral hemorrhage. Further investigation of drug or genetic therapies that selectively increase astrocyte HO-1 is warranted.

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“…Heme oxygenase (HO-1) is recognized as an important anti-oxidative stress and tissue protective enzyme that produces CO and biliverdin, and can also induce multiple anti-oxidative and anti-inflammatory signaling pathways, which significantly reduce cellular damage and protect organ function. 7) As a novel protective factor in myocardiocytes, HO-1 plays an important role in mitigating damage due to myocardial IRI through the anti-inflammatory, anti-oxidative stress, anti-apoptotic, and anti-arrhythmic effects of its products. 8) In this study, we further studied the mechanism through which AS-IV induces HO-1 expression and its related signaling pathways on an in vitro model of myocardial IRI.…”

Section: Introductionmentioning

confidence: 99%

Astragaloside IV Regulates the PI3K/Akt/HO-1 Signaling Pathway and Inhibits H9c2 Cardiomyocyte Injury Induced by Hypoxia–Reoxygenation

Yang

Zhou

Xia

et al. 2019

Biological & Pharmaceutical Bulletin

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Astragaloside IV (AS-IV) is one of the main pharmacologically active compounds found in Astragalus membranaceus. AS-IV has protective effects against ischemia-reperfusion injury (IRI), but its mechanism of action has not yet been determined. This study aims to investigate the effect of AS-IV on IRI and its effect on the phosphadylinositol 3-kinase (PI3K)/Akt/heme oxygenase (HO-1) signaling pathway through in vitro experiments. Firstly, a cell culture model of myocardiocyte hypoxia-reoxygenation (H/R) injury was replicated. After AS-IV treatment, cell viability, reactive oxygen species (ROS) levels, as well as the content or activity of the cellular factors lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), were measured to evaluate the effect of treatment with AS-IV. The effect of AS-IV on HO-1 protein expression and nuclear factor E2-related factor 2 (Nrf2) and Bach1 protein expression was determined by Western blotting. Finally, a reversal of the effect of AS-IV treatment was observed following co-incubation with a PI3K inhibitor. Our results show that AS-IV has good protective effect on H/R injury and has anti-oxidative stress and anti-inflammatory effects. It can regulate the expression of Nrf2 and Bach1 proteins in the nucleus and promote the expression of HO-1 protein, while a PI3K inhibitor can partially reverse the above effects. This study suggests that the PI3K/Akt/HO-1 signaling pathway may be a key signaling pathway for the anti-IRI effect of AS-IV.

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Heme Oxygenase-1 and Carbon Monoxide in the Heart

Cited by 170 publications

References 221 publications

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

Astrocyte heme oxygenase-1 reduces mortality and improves outcome after collagenase-induced intracerebral hemorrhage

Astragaloside IV Regulates the PI3K/Akt/HO-1 Signaling Pathway and Inhibits H9c2 Cardiomyocyte Injury Induced by Hypoxia–Reoxygenation

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