Cardiac βARK1 inhibition prolongs survival and augments β blocker therapy in a mouse model of severe heart failure

Victoria B. Harding, Larry Jones, Robert J. Lefkowitz, Walter J. Koch, Howard A. Rockman

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215 Citations (Scopus)

Abstract

Chronic human heart failure is characterized by abnormalities in β-adrenergic receptor (βAR) signaling, including increased levels of βAR kinase 1 (βARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition of βARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic mice overexpressing a peptide inhibitor of βARK1 (βARKct) with transgenic mice overexpressing the sarcoplasmic reticulum Ca2+-binding protein, calsequestrin (CSQ). CSQ mice have a severe cardiomyopathy and markedly shortened survival (9 ± 1 weeks). In contrast, CSQ/βARKct 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/βARKct, 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/βARKct mice was substantially potentiated by chronic treatment with the βAR antagonist metoprolol (CSQ/βARKct non-treated vs. CSQ/βARKct metoprolol treated, 15 ± 1 weeks vs. 25 ± 2 weeks, P < 0.0001). Thus, overexpression of the βARKct resulted in a marked prolongation in survival and improved cardiac function in a mouse model of severe cardiomyopathy that can be potentiated with β-blocker therapy. These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of βARK1 inhibition.

Original languageEnglish
Pages (from-to)5809-5814
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number10
DOIs
StatePublished - May 8 2001

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Calsequestrin
Phosphotransferases
Heart Failure
Survival
Metoprolol
Therapeutics
Cardiomyopathies
Adrenergic Receptors
Transgenic Mice
Adrenergic Antagonists
Amberlite XAD-2 resin
Sarcoplasmic Reticulum
Dilatation
Carrier Proteins
Peptides

ASJC Scopus subject areas

  • Genetics
  • General

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Cardiac βARK1 inhibition prolongs survival and augments β blocker therapy in a mouse model of severe heart failure. / Harding, Victoria B.; Jones, Larry; Lefkowitz, Robert J.; Koch, Walter J.; Rockman, Howard A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 10, 08.05.2001, p. 5809-5814.

Research output: Contribution to journalArticle

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