Protein kinase Akt/PKB phosphorylates heme oxygenase‐1 in vitro and in vivo

Salinas, Marta; Wang, Jinling; Sagarra, Marı̀a Rosa de; Martı́n, Daniel; Rojo, Ana I.; Martı́n-Pérez, Jorge; Montellano, Paul R. Ortiz de; Cuadrado, Antonio

doi:10.1016/j.febslet.2004.10.077

Cited by 97 publications

(76 citation statements)

References 25 publications

(29 reference statements)

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“…We reported recently that HO-1 functions co-dependently with Akt to confer protection from pro-oxidant-induced injury in human aortic smooth muscle cells [25]. Moreover, HO-1 and biliverdin reductase function as phosphoproteins [20,26] and may participate in phosphorylation and activation of PI3K kinase. Here we show that the cardioprotective effect of HO-1 against I/R injury is critically dependent on Akt activity both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…HO-1 appears to interact with Akt both at transcriptional [25] the post-translational level [26]. Akt has been reported to induce HO-1 transcriptionally by promoting the activation and nuclear translocation of Nrf2, a key transcription factor involved in regulation of HO-1 gene expression [25,39,40], suggesting that Akt-mediated induction of HO-1 may represent an essential protective response to cellular stress.…”

Section: Discussionmentioning

confidence: 99%

“…Akt has been reported to induce HO-1 transcriptionally by promoting the activation and nuclear translocation of Nrf2, a key transcription factor involved in regulation of HO-1 gene expression [25,39,40], suggesting that Akt-mediated induction of HO-1 may represent an essential protective response to cellular stress. In addition, Akt phosphorylates HO-1 at serine 188 in vitro and vivo, leading to a modest increase in HO-1 activity [26]. It remains to be established whether or not HO-1 directly activates PI3K/Akt.…”

Section: Discussionmentioning

confidence: 99%

“…Akt overexpression leads to increased survival and improved myocardial function following I/R injury [21][22][23][24] in a manner similar to HO-1. Recent evidence suggests that these two enzyme systems interact both at the posttranscriptional and post-translational levels [25,26], and may function in a co-dependent function to confer cytoprotection [25]. However, it is not known whether PI3K/Akt pathway is required for the cytoprotective effects of HO-1 in myocardial I/R injury.…”

Section: Introductionmentioning

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%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…2). This increase was blocked by the mRNA synthesis inhibitor actinomycin D, suggesting transcriptional control of HO-1 protein.As HO-1 requires posttranslational modification for activity [41], HO-1 activity was also measured. An approximately threefold increase in HO-1 activity was observed 6 h postincubation (Fig.…”

mentioning

confidence: 99%

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

Iles

Dickinson

Wigley

et al. 2005

Free Radical Biology and Medicine

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Heme oxygenase-1 (HO-1) is a key cytoprotective enzyme and an established marker of oxidative stress. Increased HO-1 expression has been found in the resident macrophages in the alveolar spaces of smokers. The lipid peroxidation product 4-hydroxynonenal (HNE) is also increased in the bronchial and alveolar epithelium in response to cigarette smoke. This suggests a link between a chronic environmental stress, HNE formation, and HO-1 induction. HNE is both an agent of oxidative stress in vivo and a potent cell signaling molecule. We hypothesize that HNE acts as an endogenously produced pulmonary signaling molecule that elicits an adaptive response culminating in the induction of HO-1. Here we demonstrate that HNE increases HO-1 mRNA, protein, and activity in pulmonary epithelial cells and identify ERK as a key pathway involved. Treatment with HNE increased ERK phosphorylation, c-Fos protein, JNK phosphorylation, c-Jun phosphorylation, and AP-1 binding. Whereas inhibiting the ERK pathway with the MEK inhibitor PD98059 significantly decreased HNEmediated ERK phosphorylation, c-Fos protein induction, AP-1 binding, and HO-1 protein induction, inhibition of the ERK pathway had no effect on HNE-induced HO-1 mRNA. This suggests that ERK is involved in the increase in HO-1 through regulation of translation rather than transcription. Keywords 4-Hydroxynonenal; Oxidative stress; HO-1; MAPK signaling; Free radicals Heme oxygenase-1 (HO-1) is an important cytoprotective enzyme and widely accepted marker of oxidative stress. HO-1 catalyzes the first and rate-limiting step in the catabolism of heme, which generates equimolar amounts of biliverdin, ferrous iron, and carbon monoxide [1][2][3]. Although heme is the major substrate of HO-1, a variety of non-heme-containing agents are also strong inducers of HO-1. HO-1 has been shown to respond to a number of proinflammatory cytokines, including TNF-α, . HO-1 is also induced by a variety of agents NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript that cause oxidative stress and/or in response to environmental stress [5][6][7][8]. For example, increased HO-1 expression has recently been found in the alveolar spaces in the resident macrophages of smokers [9]. Once induced, HO-1 provides protection against multiple types of tissue injury [10][11][12][13]; specific to the lung, overexpression of HO-1 in pulmonary epithelial cells has been shown to protect against oxygen toxicity [14]. In contrast, HO-1 deficiency in mice (HO-1 −/− ) increases susceptibility to inflammatory lung injury [15], as does HO-1 deficiency in humans [16]. Although the precise mechanisms by which HO-1 exerts its cytoprotective effects are not known, there is mounting evidence that carbon monoxide plays a key role in this process. For thorough reviews of the recent literature see [17,18].Another characteristic of oxidative stress is the formation of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). HNE has been shown to increase HO-1 in the cell [19,20], but the mechanism(s...

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Degradation of heme oxygenase‐1 by the immunoproteasome in astrocytes: A potential interferon‐γ‐dependent mechanism contributing to HIV neuropathogenesis

Kovacsics

Gill

Ambegaokar

et al. 2017

Glia

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Induction of the detoxifying enzyme heme oxygenase-1 (HO-1) is a critical protective host response to cellular injury associated with inflammation and oxidative stress. We previously found that HO-1 protein expression is reduced in brains of HIV-infected individuals with HIV-associated neurocognitive disorders (HAND) and in HIV-infected macrophages, where this reduction associates with enhanced glutamate release and neurotoxicity. Because HIV-infected macrophages are a small component of the cellular content of the brain, the reduction of macrophage HO-1 expression likely accounts for a small portion of brain HO-1 loss in HIV infection. We therefore investigated the contribution of astrocytes, the major pool of brain HO-1. We identified immunoproteasome-mediated HO-1 degradation in astrocytes as a second possible mechanism of brain HO-1 loss in HIV infection. We demonstrate that prolonged exposure of human fetal astrocytes to interferon-gamma (IFNγ), an HIV-associated CNS immune activator, selectively reduces expression of HO-1 protein without a concomitant reduction in HO-1 RNA, increases expression of immunoproteasome subunits, and decreases expression of constitutive proteasome subunits, consistent with a shift towards increased immunoproteasome activity. In HIV-infected brain HO-1 protein reduction also associates with increased HO-1 RNA expression and increased immunoproteasome expression. Finally, we show that IFNγ treatment of astrocytic cells reduces HO-1 protein half-life in a proteasome-dependent manner. Our data thus suggest unique causal links among HIV infection, IFNγ-mediated immunoproteasome induction, and enhanced HO-1 degradation, which likely contribute to neurocognitive impairment in HAND. Such IFNγ-mediated HO-1 degradation should be further investigated for a role in neurodegeneration in inflammatory brain conditions.

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Protein kinase Akt/PKB phosphorylates heme oxygenase‐1 in vitro and in vivo

Cited by 97 publications

References 25 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

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

Degradation of heme oxygenase‐1 by the immunoproteasome in astrocytes: A potential interferon‐γ‐dependent mechanism contributing to HIV neuropathogenesis

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