Activation of Intrinsic and Extrinsic Proapoptotic Signaling Pathways in Interleukin-18-mediated Human Cardiac Endothelial Cell Death

Chandrasekar, Bysani; Vemula, Kirankumar; Surabhi, Rama Mohan; Li‐Weber, Min; Owen‐Schaub, Laurie B.; Jensen, Liselotte E.; Mummidi, Srinivas

doi:10.1074/jbc.m313980200

Cited by 114 publications

(132 citation statements)

References 67 publications

(83 reference statements)

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“…Non-transformed human cardiac microvascular endothelial cells (EC) were obtained from ScienCell Research Laboratories (San Diego, CA) and cultured as previously described [11,12]. The cells were grown in EC medium (ECM) supplied by the manufacturer and supplemented with 5% serum (complete medium).…”

Section: Cell Culturementioning

confidence: 99%

“…Electrophoretic mobility shift (EMSA), ELISA, reporter assays NF-κB DNA-binding activity in nuclear protein extracts was analyzed by EMSA [9][10][11][12]. The following double-stranded oligonucleotides were used: consensus, 5′-AGTTGAGGGGACTTTCCCAGGC-3′; mutant, 5′-AGTTGAGGCGACTTTCCCAGGC-3′ (Santa Cruz Biotechnology, Santa Cruz, CA).…”

Section: Adenoviral Transductionmentioning

confidence: 99%

“…IL-18 is a pleiotropic cytokine that promotes inflammation, hypertrophy, mitogenesis, and apoptosis, depending on the cell type [9][10][11]. As a pro-apoptotic cytokine, IL-18 induces endothelial cell death via activation of both the intrinsic and extrinsic pro-apoptotic signaling pathways [11].…”

Section: Introductionmentioning

confidence: 99%

“…As a pro-apoptotic cytokine, IL-18 induces endothelial cell death via activation of both the intrinsic and extrinsic pro-apoptotic signaling pathways [11]. In these cells, IL-18 suppresses the pro-survival factor Akt and stimulates NF-κB-dependent PTEN induction and cell death [12].…”

Section: Introductionmentioning

confidence: 99%

“…HO-1 is induced by various noxious stimuli that include endotoxin, oxidative stress, cytokines, and hemin, where its induction exerts antioxidant and cytoprotective effects [17]. Since IL-18 induces endothelial cell death [11,12], we hypothesized that HO-1 induction or HO-1 overexpression may block IL-18-mediated endothelial cell death. Furthermore, given that IL-18 suppresses Akt and induces PTEN in an NF-κB-dependent manner, we further hypothesized that HO-1 may inhibit cell death via suppression of NF-κB-PTEN signaling and restoration of Akt activation.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Cell Culturementioning

confidence: 99%