Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells

2015 ◽  
Vol 128 (9) ◽  
pp. 567-578 ◽  
Author(s):  
Yi Zhao ◽  
Ulf Lützen ◽  
Jürgen Fritsch ◽  
Maaz Zuhayra ◽  
Stefan Schütze ◽  
...  
Keyword(s):  
Cell Death ◽  
Receptor Agonist ◽  
Uterine Leiomyosarcoma ◽  
At2 Receptor ◽  
Cytotoxic Effects ◽  
High Affinity ◽  
Compound 21 ◽  
Angiotensin Type ◽  
At2 Receptors

The angiotensin type 2 (AT2) receptor is substantially over-expressed in quiescent human uterine leiomyosarcoma cells and displays high densities in mitochondria. The high-affinity, non-peptide AT2 receptor agonist, Compound 21 exerts profound cytotoxic effects in these cells.

scholarly journals Compound 21 (C21), a Selective Angiotensin Type 2 (AT 2 ) Receptor Agonist Attenuates Bleomycin induced Alveolar Epithelial Cell Death

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Armen Nalbandyan ◽  
Anitha Shenoy ◽  
Ulrike Muscha Steckelings ◽  
Michael Katovich ◽  
Vinayak Shenoy
Keyword(s):  
Cell Death ◽  
Epithelial Cell ◽  
Receptor Agonist ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Compound 21 ◽  
Epithelial Cell Death ◽  
Angiotensin Type

Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach

2018 ◽  
Vol 132 (5) ◽  
pp. 581-593 ◽  
Author(s):  
Douglas M. Bennion ◽  
Chad H. Jones ◽  
Alex N. Dang ◽  
Jacob Isenberg ◽  
Justin T. Graham ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Angiotensin Ii ◽  
Receptor Agonist ◽  
At2 Receptor ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Receptor Agonists ◽  
Compound 21 ◽  
Neuroprotective Actions

Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor (AT2 receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT2 receptor agonists are blood–brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT2 receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4–9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.

scholarly journals Angiotensin Type 2 Receptor Agonist Compound 21 Reduces Vascular Injury and Myocardial Fibrosis in Stroke-Prone Spontaneously Hypertensive Rats

Hypertension ◽  
2012 ◽  
Vol 59 (2) ◽  
pp. 291-299 ◽  
Author(s):  
Asia Rehman ◽  
Avshalom Leibowitz ◽  
Naoki Yamamoto ◽  
Yohann Rautureau ◽  
Pierre Paradis ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Vascular Injury ◽  
Receptor Agonist ◽  
Spontaneously Hypertensive Rats ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Angiotensin Type 2 Receptor ◽  
Compound 21 ◽  
Angiotensin Type

scholarly journals Anti‐inflammatory action of angiotensin‐(1–7) and the angiotensin type 2 receptor agonist Compound 21 in hypothalamic microglia

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Meng Liu ◽  
Peng Shi ◽  
Ulrike Muscha Steckelings ◽  
Colin Sumners
Keyword(s):  
Receptor Agonist ◽  
Angiotensin Type 2 Receptor ◽  
Compound 21 ◽  
Anti Inflammatory ◽  
Inflammatory Action ◽  
Angiotensin Type

scholarly journals The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke

2014 ◽  
Vol 81 ◽  
pp. 134-141 ◽  
Author(s):  
Jason P. Joseph ◽  
Adam P. Mecca ◽  
Robert W. Regenhardt ◽  
Douglas M. Bennion ◽  
Vermali Rodríguez ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Receptor Agonist ◽  
Endothelin 1 ◽  
Angiotensin Type 2 Receptor ◽  
Compound 21 ◽  
Angiotensin Type

scholarly journals Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury

2017 ◽  
Vol 799 ◽  
pp. 128-134 ◽  
Author(s):  
Abdelrahman Y. Fouda ◽  
Bindu Pillai ◽  
Krishnan M. Dhandapani ◽  
Adviye Ergul ◽  
Susan C. Fagan
Keyword(s):  
Receptor Agonist ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Interleukin 10 ◽  
Angiotensin Type 2 Receptor ◽  
Compound 21 ◽  
Angiotensin Type

scholarly journals Mas mediated cerebroprotective action of the angiotensin type 2 receptor agonist Compound 21 in ischemic stroke.

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Neal Anil Patel ◽  
Jason Joseph ◽  
David Pioquinto ◽  
Jacob Ludin ◽  
David Greenstein ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Receptor Agonist ◽  
Angiotensin Type 2 Receptor ◽  
Compound 21 ◽  
Angiotensin Type

Abstract 31: The Angiotensin Type 2-receptor Agonist, Compound 21, Provides Neuroprotection After Ischemia Reperfusion Injury Through Interleukin 10 Upregulation

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Abdelrahman Y Fouda ◽  
Ahmed Alhusban ◽  
Adviye Ergul ◽  
Susan C Fagan
Keyword(s):  
Infarct Size ◽  
Receptor Agonist ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Behavioral Outcome ◽  
Compound 21 ◽  
Angiotensin Type

Introduction: We and others have shown that the angiotensin type 2 (AT2) receptor agonist, compound 21 (C21), provides neuroprotection and enhances recovery in rodent stroke models yet the mechanism involved is not known. Moreover, C21 treatment is associated with an anti-inflammatory response. Here we tested the hypothesis that C21 mediates neuroprotection by upregulating the neuroprotective and anti-inflammatory cytokine interleukin (IL)-10. Methods: Wistar rats (n=16) were subjected to 3 h MCA suture occlusion and treated at reperfusion with C21 (0.03 mg/kg) ± IL-10 neutralizing antibody (0.1 μg/kg) both given I.P. Endpoints at 24 h included: Infarct size, behavioral outcome, and molecular analysis. Primary rat neurons were used to test the direct neuroprotective effect of C21 in vitro. Results (Table): C21 treatment upregulated IL-10 expression (1797±89 vs 1333±84 pg/mg) and increased IL-10 downstream survival signals, STAT3 and AKT phosphorylation, in the stroked hemisphere compared to saline. Anti-IL-10 co-treatment blocked the C21 induced reduction in infarct size and inflammatory/apoptotic markers, and blunted the improvement in behavioral outcome, as well as survival signal activation. In vitro (n=4), C21 treatment failed to directly protect ischemic neurons against oxygen glucose deprivation/reperfusion (OGD/R) insult as measured by LDH release (other cell death markers are to be analyzed), but was able to upregulate IL-10 in normoxic neurons (0.3±0.02 vs 0.23±0.01) suggesting a potential indirect neuroprotective effect. Conclusion: C21 provides acute neuroprotection after ischemia reperfusion injury through neuronal IL-10 upregulation. Further understanding of the mechanism of action will pave the way for translating C21 and future AT2 agonists to the clinical stroke setting.

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