Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 10, Pages 5809-5814Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.091102398
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Funding
- NHLBI NIH HHS [R37 HL061690, R01 HL016037, HL61558, HL16037, R01 HL028556, HL61690, HL28556, R01 HL061690] Funding Source: Medline
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Chronic human heart failure is characterized by abnormalities in beta -adrenergic receptor (beta AR) signaling, including increased levels of beta AR kinase 1 (beta ARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition of beta ARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic mice overexpressing a peptide inhibitor of beta ARK1 (beta ARKct) 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/beta ARKct 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/beta ARKct, 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/beta ARKct mice was substantially potentiated by chronic treatment with the beta AR antagonist metoprolol (CSQ/beta ARKct nontreated vs. CSQ/beta ARKct metoprolol treated, 15 +/- 1 weeks vs. 25 +/- 2 weeks, P < 0.0001). Thus, overexpression of the beta ARKct resulted in a marked prolongation in survival and improved cardiac function in a mouse model of severe cardiomyopathy that can be potentiated with P-blocker therapy. These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of beta ARK1 inhibition.
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