Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase

Hafezi-Moghadam, Ali; Simoncini, Tommaso; Yang, Zequan; Limbourg, Florian P.; Plumier, Jean-Christophe; Rebsamen, Michela; Hsieh, Chung-Ming; Chui, Dao-Shan; Thomas, Kerry; Prorock, Alyson; Laubach, Victor E.; Moskowitz, Michael A.; French, Brent A.; Ley, Klaus; Liao, James K.

doi:10.1038/nm0502-473

Cited by 506 publications

(351 citation statements)

References 42 publications

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“…In a genomics screen of acute lymphoblastic leukemia (ALL) cells, genes associated with the PI3-kinase/AKT pathway were highly enriched in a gene signature of GC-resistance [42]. A physical interaction between the GR and the p85 regulatory sub-unit of PI3-kinase has been reported in a number of different cell systems and this interaction was shown to counteract the tumorigenicity of activated AKT in a mouse skin cancer transgenic model [43][44][45]. Interaction of nuclear hormone receptors with members of the FOXO protein family downstream of PI3-kinase/ AKT has also been reported.…”

Section: Discussionmentioning

confidence: 99%

Dual regulation of glucocorticoid-induced leucine zipper (GILZ) by the glucocorticoid receptor and the PI3-kinase/AKT pathways in multiple myeloma

Grugan

Singhal

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Glucocorticoids (GCs) are effective therapeutics commonly used in multiple myeloma (MM) treatment. Clarifying the pathway of GC-induced apoptosis is crucial to understanding the process of drug resistance and to the development of new targets for MM treatment. We have previously published results of a micro-array identifying glucocorticoid-induced leucine zipper (GILZ) as GC-regulated gene in MM.1S cells. Consistent with those results, GCs increased GILZ in MM cell lines and patient samples. Reducing the levels of GILZ with siRNA decreased GC-induced cell death suggesting GILZ may mediate GC-killing. We conducted a screen to identify other pathways that affect GILZ regulation and report that inhibitors of PI3-kinase/AKT enhanced GILZ expression in MM cell lines and clinical samples. The combination of dexamethasone (Dex) and LY294002, wortmannin, triciribine, or AKT inhibitor VIII dramatically up regulated GILZ levels and enhanced apoptosis. Addition of interleukin-6 (IL-6) or insulin-like growth factor (IGF1), both which activate the PI3-kinase/AKT pathway and inhibit GC killing, blocked up regulation of GILZ by GC and PI3-kinase/AKT inhibitors. In summary, these results identify GILZ as a mediator of GC killing, indicate a role of PI3-kinase/AKT in controlling GILZ regulation and suggest that the combination of PI3-kinase/AKT inhibitors and GCs may be a beneficial MM treatment.

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Section: Discussionmentioning

confidence: 99%

Dual regulation of glucocorticoid-induced leucine zipper (GILZ) by the glucocorticoid receptor and the PI3-kinase/AKT pathways in multiple myeloma

Grugan

Singhal

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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“…Glucocorticoids have been shown to activate PI3K in endothelial cells (Hafezi-Moghadam et al, 2002). The activity of PI3K was measured to address whether CT treatment resulted in activation of PI3K/AKT signaling pathway in cardiomyocytes.…”

Section: Lack Of Pi3k/akt Signaling Pathway Activation By Ct Treatmentmentioning

confidence: 99%

LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

Sun

Шевелева

et al. 2008

Toxicology and Applied Pharmacology

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Glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT) induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K/AKT signaling pathway whereas LY29 and WM decreased the activity of PI3K. LY303511 (LY30), a structural analogue and a negative control for PI3K inhibitory activity of LY29, also suppressed COX-2 induction. These data suggest PI3K independent mechanisms in regulating CT induced COX-2 expression. LY29 and LY30 do not inhibit glucocorticoid receptor transactivity. Both compounds have been reported to inhibit Casein Kinase 2 activity and modulate potassium and calcium levels independent of PI3K, while LY29 has been reported to inhibit mammalian Target of Rapamycin (mTOR), DNA-dependent Protein Kinase (DNA-PK). Inhibitor of Casein Kinase 2 (CK2), mTOR or DNA-PK failed to prevent CT from inducing COX-2 expression. Tetraethylammonium (TEA), a potassium channel blocker, and nimodipine, a calcium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca 2+ concentration, which can be inhibited by LY29, TEA or nimodipine. These data suggest a possible role of calcium instead of PI3K in CT induced COX-2 expression in cardiomyocytes.

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“…Recent findings suggest that there is yet another level of GR action with particular importance for the vascular system. A rapid, nontranscriptional effect of GR was found to mediate tissue protection in myocardial infarction and stroke through activation of endothelial nitric oxide synthase (eNOS), which is mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt pathway [9,10].…”

Section: Introductionmentioning

confidence: 99%

Nontranscriptional actions of the glucocorticoid receptor

Limbourg

Liao

2003

J Mol Med

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Many cellular responses to corticosteroids involve the transcriptional modulation of target genes by a prototypical nuclear receptor, the glucocorticoid receptor (GR). In the classic model of steroid hormone action GR acts as ligand-dependent transcription factor by either activating or repressing gene expression through direct interactions with DNA or other transcription factors. Recent evidence suggests an important role for nontranscriptional effects of GR in the vascular system. The nontranscriptional actions of GR involve the rapid activation of protein kinases, such as phosphatidylinositol-3 kinase and Akt, leading to the activation of endothelial nitric oxide synthase. This novel pathway of steroid hormone action protects against ischemic injury by augmenting blood flow and decreasing vascular inflammation.

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Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase

Cited by 506 publications

References 42 publications

Dual regulation of glucocorticoid-induced leucine zipper (GILZ) by the glucocorticoid receptor and the PI3-kinase/AKT pathways in multiple myeloma

Dual regulation of glucocorticoid-induced leucine zipper (GILZ) by the glucocorticoid receptor and the PI3-kinase/AKT pathways in multiple myeloma

LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

Nontranscriptional actions of the glucocorticoid receptor

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