Protection of Human Vascular Smooth Muscle Cells From H
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            O
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            -Induced Apoptosis Through Functional Codependence Between HO-1 and AKT

Brunt, Keith R.; Fenrich, Keith K.; Kiani, Gholam; Tse, M. Yat; Pang, Stephen C.; Ward, Christopher A.; Melo, Luis G.

doi:10.1161/01.atv.0000236204.37119.8d

Cited by 93 publications

(60 citation statements)

References 47 publications

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“…However, emerging evidence, suggests that HO-1 may also exert cytoprotective effects, independent of heme breakdown [38] by interacting with survival signaling pathways such as PI3K-Akt and p38. 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.…”

Section: Discussionmentioning

confidence: 98%

“…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. In addition, Akt phosphorylates HO-1 at serine 188 in vitro and vivo, leading to a modest increase in HO-1 activity [26].…”

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: 98%

Section: Discussionmentioning

confidence: 99%

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

Self Cite

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“…It is possible that HO-1 may have regulated Akt activation via two different mechanisms. Brunt et al have demonstrated functional codependence of HO-1 and Akt in HO-1 treated hydrogen peroxide-induced smooth muscle cell death [46]. Though HO-1 is regulated primarily at the transcriptional level, Akt-induced HO-1 phosphorylation resulted in increased HO-1 activity.…”

Section: Discussionmentioning

confidence: 99%

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

Zabalgoitia

Colston

Reddy

et al. 2008

Free Radical Biology and Medicine

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The objective of this study was to determine whether heme oxygenase-1 (HO-1) or heme metabolites exert cytoprotective effects on interleukin-18-mediated endothelial cell (EC) death. Treatment with IL-18 increased NF-κB activation, PTEN induction, suppressed Akt activation, and stimulated EC death. While ectopic expression of p65 enhanced PTEN transcription, adenoviral transduction of dnIκB-α, dnp65, or dnIKKβ was inhibitory. Furthermore, IL-18 suppressed HO-1 mRNA expression via enhanced mRNA degradation. Overexpression of HO-1, treatment with HO-1 inducer hemin or the CO donor Cobalt (III) protoporphyrin IX all reversed IL-18-mediated NF-κB activation, PTEN induction, Akt suppression, and EC death. Furthermore, hemin induced HO-1 expression, and HO-1 knockdown, HO-1 inhibition, or CO scavengers all reversed the pro-survival effects of hemin. In addition, the CO donors CORM-1 and CORM-3 and the heme metabolites biliverdin and bilirubin attenuated IL-18-induced EC death via a similar signaling pathway. IL-18 induced p38α MAPK activation, and suppressed p38β isoform expression. While p38α knockdown attenuated, p38β knockdown potentiated IL-18-mediated EC death. Hemin and HO-1 reversed IL-18-mediated p38α induction, and restored p38β levels. These results demonstrate that IL-18 suppresses HO-1 expression and induces EC death. HO-1 overexpression, HO-1 induction, or treatment with heme metabolites all reverse IL-18-mediated p38α MAPK and NF-κB activation, PTEN induction, Akt suppression, and EC death. Thus, HO-1 inducers and CO donors may have the therapeutic potential to effectively block IL-18 signaling and reduce IL-18-dependent vascular injury and inflammation.

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“…The apoptotic response appears to be mediated by activation of c-jun Nterminal kinase (JNK). Furthermore, in vitro studies have shown that H 2 O 2 can induce apoptosis through a protein kinase C pathway, which is antagonized by Akt and heme oxygenase-1 (Brunt et al 2006). …”

Section: Vascular Cell Apoptosismentioning

confidence: 99%

Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular Injury

Papaharalambus

Griendling

2007

Trends in Cardiovascular Medicine

289

224

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The development of vascular disease has its origins in an initial insult to the vessel wall by biological or mechanical factors. The disruption of homeostatic mechanisms leads to alteration of the original architecture of the vessel and its biological responsiveness, contributing to acute or chronic diseases such as stroke, hypertension and atherosclerosis. Endothelial dysfunction, macrophage infiltration of the vessel wall, and proliferation and migration of smooth muscle cells all involve different types of reactive oxygen species, produced by various vessel wall components. Although basic science and animal research have clearly established the role of reactive oxygen species in the progression of vascular disease, the failure of clinical trials with antioxidant compounds has underscored the need for better antioxidant therapies and a more thorough understanding of the role of reactive oxygen species in cardiovascular physiology and pathology.The fundamental processes underlying the development of vascular diseases such as atherosclerosis, restenosis and hypertensive vascular remodeling have their origins in an initial insult to the vessel wall. Such an insult may arise from mechanical disruption that occurs during percutaneous coronary angioplasty or at regions of oscillatory shear stress, or it can result from biological causes, such as hypercholesterolemia, excess free radicals, diabetes, increased concentrations of plasma homocysteine, or infectious agents. Injury promotes disruption of the homeostatic mechanisms of the endothelial protective barrier, changing its natural properties, increasing its adhesiveness to leukocytes and altering its permeability. This endothelial dysfunction also leads to the formation of vasoactive molecules, which in turn induce inflammatory genes, inactivate nitric oxide (NO • ) and its protective functions, and activate matrix metalloproteinases, leading to extracellular matrix remodeling, and increased smooth muscle cell (VSMC) growth, migration and proliferation. Each of these processes contributes to thickening of the vessel wall or the formation of lesions that can lead to hypertension, acute myocardial infarction and stroke. Reactive Oxygen Species and Vascular InjuryIn the past decade a staggering amount of evidence implicates a common denominator, reactive oxygen species (ROS), in the development of most cardiovascular diseases (Figure 1). Superoxide (O 2 •− ) and hydrogen peroxide (H 2 O 2 ) are two of the most biologically important ROS in the cardiovascular system, and are produced in vascular cells by a number of oxidases, including the NADPH oxidases (Nox) and xanthine oxidase, lipoxygenases, cytochrome p450,

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Protection of Human Vascular Smooth Muscle Cells From H ₂ O ₂ -Induced Apoptosis Through Functional Codependence Between HO-1 and AKT

Cited by 93 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

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular Injury

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Protection of Human Vascular Smooth Muscle Cells From H 2 O 2 -Induced Apoptosis Through Functional Codependence Between HO-1 and AKT

Cited by 93 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

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular Injury

Contact Info

Product

Resources

About

Protection of Human Vascular Smooth Muscle Cells From H ₂ O ₂ -Induced Apoptosis Through Functional Codependence Between HO-1 and AKT