Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB

Franziska Rompe, Metin Artuc, Anders Hallberg, Mathias Alterman, Katja Ströder, Christa Thöne-Reineke, Anne Reichenbach, Jens Schacherl, Björn Dahlöf, Michael Bader, Natalia Alenina, Markus Schwaninger, Torsten Zuberbier, Heiko Funke-Kaiser, Cosima Schmidt, Wolf-Hagen Schunck, Thomas Unger, Ulrike Muscha Steckelings

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Angiotensin II type 2 (AT(2)) receptors can be regarded as an endogenous repair system, because the AT(2) receptor is upregulated in tissue damage and mediates tissue protection. A potential therapeutic use of this system has only recently come within reach through synthesis of the first selective, orally active, nonpeptide AT(2) receptor agonist, compound 21 (C21; dissociation constant for AT(2) receptor: 0.4 nM; dissociation constant for angiotensin II type 1 receptor: >10,000 nM). This study tested AT(2) receptor stimulation with C21 as a potential future therapeutic approach for the inhibition of proinflammatory cytokines and of nuclear factor kappaB. C21 dose-dependently (1 nM to 1 micromol/L) reduced tumor necrosis factor-alpha-induced interleukin 6 levels in primary human and murine dermal fibroblasts. AT(2) receptor specificity was controlled for by inhibition with the AT(2) receptor antagonist PD123319 and by the absence of effects in AT(2) receptor-deficient cells. AT(2) receptor-coupled signaling leading to reduced interleukin 6 levels involved inhibition of nuclear factor kappaB, activation of protein phosphatases, and synthesis of epoxyeicosatrienoic acid. Inhibition of interleukin 6 promoter activity by C21 was comparable in strength to inhibition by hydrocortisone. C21 also reduced monocyte chemoattractant protein 1 and tumor necrosis factor-alpha in vitro and in bleomycin-induced toxic cutaneous inflammation in vivo. This study is the first to show the anti-inflammatory effects of direct AT(2) receptor stimulation in vitro and in vivo by the orally active, nonpeptide AT(2) receptor agonist C21. These data suggest that pharmacological AT(2) receptor stimulation may be an orally applicable future therapeutic approach in pathological settings requiring the reduction of interleukin 6 or inhibition of nuclear factor kappaB.
OriginalsprogEngelsk
TidsskriftHypertension
Vol/bind55
Udgave nummer4
Sider (fra-til)924-31
Antal sider8
ISSN0194-911X
DOI
StatusUdgivet - 2010
Udgivet eksterntJa

Fingeraftryk

Angiotensin Type 2 Receptor
Acids
Interleukin-6
Angiotensin II Type 2 Receptor Blockers
Tumor Necrosis Factor-alpha
Skin
Angiotensin Type 1 Receptor
Chemokine CCL2
Poisons
Phosphoprotein Phosphatases
Therapeutic Uses

Citer dette

Rompe, Franziska ; Artuc, Metin ; Hallberg, Anders ; Alterman, Mathias ; Ströder, Katja ; Thöne-Reineke, Christa ; Reichenbach, Anne ; Schacherl, Jens ; Dahlöf, Björn ; Bader, Michael ; Alenina, Natalia ; Schwaninger, Markus ; Zuberbier, Torsten ; Funke-Kaiser, Heiko ; Schmidt, Cosima ; Schunck, Wolf-Hagen ; Unger, Thomas ; Steckelings, Ulrike Muscha. / Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB. I: Hypertension. 2010 ; Bind 55, Nr. 4. s. 924-31.
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title = "Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB",
abstract = "Angiotensin II type 2 (AT(2)) receptors can be regarded as an endogenous repair system, because the AT(2) receptor is upregulated in tissue damage and mediates tissue protection. A potential therapeutic use of this system has only recently come within reach through synthesis of the first selective, orally active, nonpeptide AT(2) receptor agonist, compound 21 (C21; dissociation constant for AT(2) receptor: 0.4 nM; dissociation constant for angiotensin II type 1 receptor: >10,000 nM). This study tested AT(2) receptor stimulation with C21 as a potential future therapeutic approach for the inhibition of proinflammatory cytokines and of nuclear factor kappaB. C21 dose-dependently (1 nM to 1 micromol/L) reduced tumor necrosis factor-alpha-induced interleukin 6 levels in primary human and murine dermal fibroblasts. AT(2) receptor specificity was controlled for by inhibition with the AT(2) receptor antagonist PD123319 and by the absence of effects in AT(2) receptor-deficient cells. AT(2) receptor-coupled signaling leading to reduced interleukin 6 levels involved inhibition of nuclear factor kappaB, activation of protein phosphatases, and synthesis of epoxyeicosatrienoic acid. Inhibition of interleukin 6 promoter activity by C21 was comparable in strength to inhibition by hydrocortisone. C21 also reduced monocyte chemoattractant protein 1 and tumor necrosis factor-alpha in vitro and in bleomycin-induced toxic cutaneous inflammation in vivo. This study is the first to show the anti-inflammatory effects of direct AT(2) receptor stimulation in vitro and in vivo by the orally active, nonpeptide AT(2) receptor agonist C21. These data suggest that pharmacological AT(2) receptor stimulation may be an orally applicable future therapeutic approach in pathological settings requiring the reduction of interleukin 6 or inhibition of nuclear factor kappaB.",
author = "Franziska Rompe and Metin Artuc and Anders Hallberg and Mathias Alterman and Katja Str{\"o}der and Christa Th{\"o}ne-Reineke and Anne Reichenbach and Jens Schacherl and Bj{\"o}rn Dahl{\"o}f and Michael Bader and Natalia Alenina and Markus Schwaninger and Torsten Zuberbier and Heiko Funke-Kaiser and Cosima Schmidt and Wolf-Hagen Schunck and Thomas Unger and Steckelings, {Ulrike Muscha}",
year = "2010",
doi = "10.1161/HYPERTENSIONAHA.109.147843",
language = "English",
volume = "55",
pages = "924--31",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams & Wilkins",
number = "4",

}

Rompe, F, Artuc, M, Hallberg, A, Alterman, M, Ströder, K, Thöne-Reineke, C, Reichenbach, A, Schacherl, J, Dahlöf, B, Bader, M, Alenina, N, Schwaninger, M, Zuberbier, T, Funke-Kaiser, H, Schmidt, C, Schunck, W-H, Unger, T & Steckelings, UM 2010, 'Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB', Hypertension, bind 55, nr. 4, s. 924-31. https://doi.org/10.1161/HYPERTENSIONAHA.109.147843

Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB. / Rompe, Franziska; Artuc, Metin; Hallberg, Anders; Alterman, Mathias; Ströder, Katja; Thöne-Reineke, Christa; Reichenbach, Anne; Schacherl, Jens; Dahlöf, Björn; Bader, Michael; Alenina, Natalia; Schwaninger, Markus; Zuberbier, Torsten; Funke-Kaiser, Heiko; Schmidt, Cosima; Schunck, Wolf-Hagen; Unger, Thomas; Steckelings, Ulrike Muscha.

I: Hypertension, Bind 55, Nr. 4, 2010, s. 924-31.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB

AU - Rompe, Franziska

AU - Artuc, Metin

AU - Hallberg, Anders

AU - Alterman, Mathias

AU - Ströder, Katja

AU - Thöne-Reineke, Christa

AU - Reichenbach, Anne

AU - Schacherl, Jens

AU - Dahlöf, Björn

AU - Bader, Michael

AU - Alenina, Natalia

AU - Schwaninger, Markus

AU - Zuberbier, Torsten

AU - Funke-Kaiser, Heiko

AU - Schmidt, Cosima

AU - Schunck, Wolf-Hagen

AU - Unger, Thomas

AU - Steckelings, Ulrike Muscha

PY - 2010

Y1 - 2010

N2 - Angiotensin II type 2 (AT(2)) receptors can be regarded as an endogenous repair system, because the AT(2) receptor is upregulated in tissue damage and mediates tissue protection. A potential therapeutic use of this system has only recently come within reach through synthesis of the first selective, orally active, nonpeptide AT(2) receptor agonist, compound 21 (C21; dissociation constant for AT(2) receptor: 0.4 nM; dissociation constant for angiotensin II type 1 receptor: >10,000 nM). This study tested AT(2) receptor stimulation with C21 as a potential future therapeutic approach for the inhibition of proinflammatory cytokines and of nuclear factor kappaB. C21 dose-dependently (1 nM to 1 micromol/L) reduced tumor necrosis factor-alpha-induced interleukin 6 levels in primary human and murine dermal fibroblasts. AT(2) receptor specificity was controlled for by inhibition with the AT(2) receptor antagonist PD123319 and by the absence of effects in AT(2) receptor-deficient cells. AT(2) receptor-coupled signaling leading to reduced interleukin 6 levels involved inhibition of nuclear factor kappaB, activation of protein phosphatases, and synthesis of epoxyeicosatrienoic acid. Inhibition of interleukin 6 promoter activity by C21 was comparable in strength to inhibition by hydrocortisone. C21 also reduced monocyte chemoattractant protein 1 and tumor necrosis factor-alpha in vitro and in bleomycin-induced toxic cutaneous inflammation in vivo. This study is the first to show the anti-inflammatory effects of direct AT(2) receptor stimulation in vitro and in vivo by the orally active, nonpeptide AT(2) receptor agonist C21. These data suggest that pharmacological AT(2) receptor stimulation may be an orally applicable future therapeutic approach in pathological settings requiring the reduction of interleukin 6 or inhibition of nuclear factor kappaB.

AB - Angiotensin II type 2 (AT(2)) receptors can be regarded as an endogenous repair system, because the AT(2) receptor is upregulated in tissue damage and mediates tissue protection. A potential therapeutic use of this system has only recently come within reach through synthesis of the first selective, orally active, nonpeptide AT(2) receptor agonist, compound 21 (C21; dissociation constant for AT(2) receptor: 0.4 nM; dissociation constant for angiotensin II type 1 receptor: >10,000 nM). This study tested AT(2) receptor stimulation with C21 as a potential future therapeutic approach for the inhibition of proinflammatory cytokines and of nuclear factor kappaB. C21 dose-dependently (1 nM to 1 micromol/L) reduced tumor necrosis factor-alpha-induced interleukin 6 levels in primary human and murine dermal fibroblasts. AT(2) receptor specificity was controlled for by inhibition with the AT(2) receptor antagonist PD123319 and by the absence of effects in AT(2) receptor-deficient cells. AT(2) receptor-coupled signaling leading to reduced interleukin 6 levels involved inhibition of nuclear factor kappaB, activation of protein phosphatases, and synthesis of epoxyeicosatrienoic acid. Inhibition of interleukin 6 promoter activity by C21 was comparable in strength to inhibition by hydrocortisone. C21 also reduced monocyte chemoattractant protein 1 and tumor necrosis factor-alpha in vitro and in bleomycin-induced toxic cutaneous inflammation in vivo. This study is the first to show the anti-inflammatory effects of direct AT(2) receptor stimulation in vitro and in vivo by the orally active, nonpeptide AT(2) receptor agonist C21. These data suggest that pharmacological AT(2) receptor stimulation may be an orally applicable future therapeutic approach in pathological settings requiring the reduction of interleukin 6 or inhibition of nuclear factor kappaB.

U2 - 10.1161/HYPERTENSIONAHA.109.147843

DO - 10.1161/HYPERTENSIONAHA.109.147843

M3 - Journal article

VL - 55

SP - 924

EP - 931

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 4

ER -