Document Detail


β-Arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury.
MedLine Citation:
PMID:  22886417     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Ki-Seok Kim; Dennis Abraham; Barbara Williams; Jonathan D Violin; Lan Mao; Howard A Rockman
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2012-08-10
Journal Detail:
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:
Created Date:  2012-10-16     Completed Date:  2012-12-26     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1001-10     Citation Subset:  IM    
Affiliation:
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Acute Coronary Syndrome / 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:
HL56687/HL/NHLBI NIH HHS; HL75443/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
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
Comments/Corrections

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