Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice

Yet, Shaw‐Fang; Perrella, Mark A.; Layne, Matthew D.; Hsieh, Chung-Ming; Maemura, Koji; Kobzik, Lester; Wiesel, Philippe; Christou, Helen; Kourembanas, Stella; Lee, Mu-En

doi:10.1172/jci6163

Cited by 385 publications

(312 citation statements)

References 47 publications

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“…Heme oxygenase-1 plays a central role in myocardial protection from I/R injury. The enzyme is induced several fold by hypoxia and reoxygenation [28,29], and genetic mouse models of HO-1 deficiency have greater propensity towards ischemia and hyperoxia induced tissue injury [12,13]. Moreover, pre-emptive delivery of HO-1 gene markedly reduces infarct size following acute I/R [10,11], suggesting that enhanced basal level of HO-1 preconditions the myocardium [12,30] and renders it resistant to subsequent episodes of I/R injury [14].…”

Section: Discussionmentioning

confidence: 99%

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Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

Pachori

Smith

McDonald

et al. 2007

Journal of Molecular and Cellular Cardiology

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Heme-oxygenase-1 (HO-1), a stress-inducible protein, is an important cytoprotective agent in various models of ischemia/reperfusion (I/R) injury. However, the role of downstream mediators involved in HO-1 induced cytoprotection is not clear. In the current study we investigated the role of biliverdin reductase, an enzyme involved in the conversion of HO-1 derived biliverdin into bilirubin and the PI3K/Akt pathway in mediating the cytoprotective effects of HO-1 against hypoxia and reoxygenation (H/R) injury in vitro and in vivo. H9c2 cardiomyocytes were transfected with a plasmid expressing HO-1 or LacZ and exposed to 24 hours of hypoxia followed by 12 hours of reoxygenation. At the end of reoxygenation, reactive oxygen species generation was determined using CM-H 2 DCFDA dye and apoptosis was assessed by TUNEL, caspase activity and Bad phosphorylation. p85 and Akt phosphorylation were determined using cell based ELISA and phospho-specific antibodies, respectively. HO-1 overexpression increased phosphorylation of the regulatory subunit of the PI3K (p85α) and downstream effector Akt in H9c2 cells, leading to decreased ROS and apoptosis. Furthermore, cardiac specific HO-1 expression increased basal phosphorylated Akt levels and decreased infarct size in response to LAD ligation and release induced I/R injury. Conversely, PI3K inhibition reversed the effects of HO-1 on Akt phosphorylation, cell death and infarct size. In addition, knockdown of biliverdin reductase (BVR) expression with siRNA attenuated HO-1 induced Akt phosphorylation and increased H/R-induced apoptosis of H9c2 cells. Co-immunoprecipitation revealed protein-protein interaction between BVR and the phosphorylated p85 subunit of the PI3 kinase. Taken together, these results suggest that the enzyme biliverdin reductase plays an important role in mediating cytoprotective effects of HO-1. This effect is mediated, at least in part, via activation of the PI3K/Akt pathway.

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Section: Discussionmentioning

confidence: 99%

“…Conversely, reduced HO-1 levels increase susceptibility to injury in a variety of stress conditions. For example, HO-1 null mice show impaired ventricular function [12] and increased incidence of right ventricular infarcts with mural thrombi in response to chronic pulmonary hypoxia [13].…”

Section: Introductionmentioning

confidence: 99%

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

Pachori

Smith

McDonald

et al. 2007

Journal of Molecular and Cellular Cardiology

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“…The antiapoptotic effect of HO-1 is reversed in the presence of HO-1 inhibitors or in cells overexpressing antisense HO-1 (Petrache et al, 2000). Inhibition of apoptosis following the expression of HO-1 has also been reported in animal models of inflammation, ischemia-reperfusion, hypoxia, and organ transplantation while inhibition of HO-1 activity or deletion of the HO-1 gene promotes apoptosis in these animal models (Hancock et al, 1998;Soares et al, 1998;Yet et al, 1999;Ke et al, 2002;Vulapalli et al, 2002).…”

Section: Ho-1 and Cell Deathmentioning

confidence: 91%

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Durante

2003

Journal Cellular Physiology

143

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Heme oxygenase-1 (HO-1) catalyzes the degradation of heme to carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently metabolized to bilirubin by the enzyme biliverdin reductase. Although interest in HO-1 originally centered on its heme-degrading function, recent findings indicate that HO-1 exerts other biologically important actions. Emerging evidence suggests that HO-1 plays a critical role in growth regulation. Deletion of the HO-1 gene or inhibition of HO-1 activity results in growth retardation and impaired fetal development, whereas HO-1 overexpression increases body size. Although the mechanisms responsible for the growth promoting properties of HO-1 are not well established, HO-1 can indirectly influence growth by regulating the synthesis of growth factors and by modulating the delivery of oxygen or nutrients to specific target tissues. In addition, HO-1 exerts important effects on critical determinants of tissue size, including cell proliferation, apoptosis, and hypertrophy. However, the actions of HO-1 are highly variable and may reflect a role for HO-1 in maintaining tissue homeostasis. Considerable evidence supports a crucial role for HO-1 in blocking the growth of vascular smooth muscle cells (SMCs). This antiproliferative effect of HO-1 is mediated primarily via the release of CO, which inhibits vascular SMC growth via multiple pathways. Pharmacologic or genetic approaches targeting HO-1 or CO to the blood vessel wall may represent a promising, novel therapeutic approach in treating vascular proliferative disorders.

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“…If such an inhibitory effect also occurs in vivo, transcription of NPAS2-BMAL1-target genes should increase when endogenous CO levels are decreased. Because heme oxygenase activity is the primary source of endogenous CO, and Ho-1 is the dominant paralog in the periphery 13 , we measured circadian transcript levels of CLOCK(NPAS2)-BMAL1-target genes in primary fibroblasts from Ho-1-knockout mice 14 . Indeed, transcript levels of clock genes containing functional promoter E boxes, such as Dbp, Rev-Erb and Per2, were substantially upregulated, whereas transcription of Bmal1 was downregulated during periods in which levels of the repressor REV-ERB was high (Fig.…”

Section: Heme Degradation Is Regulated By the Circadian Clockmentioning

confidence: 99%

“…Gene ontology analysis revealed significant enrichment of genes involved in metabolic processes in cluster 1, whereas in the Ho-1-dominated cluster 4, the significant GO terms reflect known roles of Ho-1 in cytoprotection and immune response 13,14 (Fig. 6b).…”

Section: Heme Oxygenase Depletion Alters Glucose Homeostasismentioning

confidence: 99%

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

Klemz

Reischl

Wallach

et al. 2016

Nat Struct Mol Biol

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Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice

Cited by 385 publications

References 47 publications

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

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