RGD Reference Report - Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. - Rat Genome Database

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Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure.

Authors: Harding, VB  Jones, LR  Lefkowitz, RJ  Koch, WJ  Rockman, HA 
Citation: Harding VB, etal., Proc Natl Acad Sci U S A 2001 May 8;98(10):5809-14. Epub 2001 May 1.
RGD ID: 737776
Pubmed: PMID:11331748   (View Abstract at PubMed)
PMCID: PMC33295   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.091102398   (Journal Full-text)

Chronic human heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased levels of betaAR kinase 1 (betaARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition of betaARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic mice overexpressing a peptide inhibitor of betaARK1 (betaARKct) with transgenic mice overexpressing the sarcoplasmic reticulum Ca(2+)-binding protein, calsequestrin (CSQ). CSQ mice have a severe cardiomyopathy and markedly shortened survival (9 +/- 1 weeks). In contrast, CSQ/betaARKct mice exhibited a significant increase in mean survival age (15 +/- 1 weeks; P < 0.0001) and showed less cardiac dilation, and cardiac function was significantly improved (CSQ vs. CSQ/betaARKct, left ventricular end diastolic dimension 5.60 +/- 0.17 mm vs. 4.19 +/- 0.09 mm, P < 0.005; % fractional shortening, 15 +/- 2 vs. 36 +/- 2, P < 0.005). The enhancement of the survival rate in CSQ/betaARKct mice was substantially potentiated by chronic treatment with the betaAR antagonist metoprolol (CSQ/betaARKct nontreated vs. CSQ/betaARKct metoprolol treated, 15 +/- 1 weeks vs. 25 +/- 2 weeks, P < 0.0001). Thus, overexpression of the betaARKct resulted in a marked prolongation in survival and improved cardiac function in a mouse model of severe cardiomyopathy that can be potentiated with beta-blocker therapy. These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of betaARK1 inhibition.




  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
GRK2Humancongestive heart failure  ISOGrk2 (Mus musculus) RGD 
Grk2Ratcongestive heart failure  ISOGrk2 (Mus musculus) RGD 
Grk2Mousecongestive heart failure  IAGP  RGD 


Genes (Rattus norvegicus)
Grk2  (G protein-coupled receptor kinase 2)

Genes (Mus musculus)
Grk2  (G protein-coupled receptor kinase 2)

Genes (Homo sapiens)
GRK2  (G protein-coupled receptor kinase 2)