| β-Arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury. | |
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MedLine Citation:
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PMID: 22886417 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Pharmacological blockade of the ANG II type 1 receptor (AT1R) is a common therapy for treatment of congestive heart failure and hypertension. Increasing evidence suggests that selective engagement of β-arrestin-mediated AT1R signaling, referred to as biased signaling, promotes cardioprotective signaling. Here, we tested the hypothesis that a β-arrestin-biased AT1R ligand TRV120023 would confer cardioprotection in response to acute cardiac injury compared with the traditional AT1R blocker (ARB), losartan. TRV120023 promotes cardiac contractility, assessed by pressure-volume loop analyses, while blocking the effects of endogenous ANG II. Compared with losartan, TRV120023 significantly activates MAPK and Akt signaling pathways. These hemodynamic and biochemical effects were lost in β-arrestin-2 knockout (KO) mice. In response to cardiac injury induced by ischemia reperfusion injury or mechanical stretch, pretreatment with TRV120023 significantly diminishes cell death compared with losartan, which did not appear to be cardioprotective. This cytoprotective effect was lost in β-arrestin-2 KO mice. The β-arrestin-biased AT1R ligand, TRV120023, has cardioprotective and functional properties in vivo, which are distinct from losartan. Our data suggest that this novel class of drugs may provide an advantage over conventional ARBs by supporting cardiac function and reducing cellular injury during acute cardiac injury. |
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Authors:
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Ki-Seok Kim; Dennis Abraham; Barbara Williams; Jonathan D Violin; Lan Mao; Howard A Rockman |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural Date: 2012-08-10 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: 303 ISSN: 1522-1539 ISO Abbreviation: Am. J. Physiol. Heart Circ. Physiol. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-16 Completed Date: 2012-12-26 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H1001-10 Citation Subset: IM |
Affiliation:
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Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acute Coronary Syndrome
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drug therapy*,
metabolism,
pathology Acute Disease Adaptor Proteins, Signal Transducing / antagonists & inhibitors, metabolism* Angiotensin II Type 1 Receptor Blockers / pharmacology Animals Apoptosis / drug effects, physiology Arrestins / genetics, metabolism* Cardiotonic Agents / pharmacology* Cell Survival / drug effects, physiology Disease Models, Animal Losartan / pharmacology* Mice Mice, Inbred C57BL Mice, Knockout Myocardial Contraction / drug effects, physiology Myocardium / metabolism, pathology Oligopeptides / pharmacology* Signal Transduction / drug effects, physiology |
| Grant Support | |
ID/Acronym/Agency:
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HL56687/HL/NHLBI NIH HHS; HL75443/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/Agtrap protein, mouse; 0/Angiotensin II Type 1 Receptor Blockers; 0/Arrestins; 0/Cardiotonic Agents; 0/Oligopeptides; 0/beta-arrestin; 0/sarcosine-arginyl-valyl-tyrosyl-lysyl-histidyl-prolyl-alanine; 114798-26-4/Losartan |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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