Cardiac βARK1 Inhibition Prolongs Survival and Augments β Blocker Therapy in a Mouse Model of Severe Heart Failure

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 10; pp. 5809 - 5814
• Main Authors: Harding, Victoria B., Jones, Larry R., Lefkowitz, Robert J., Koch, Walter J., Rockman, Howard A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08-05-2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Adrenergic beta-Antagonists - therapeutic use; Animals; beta-Adrenergic Receptor Kinases; Biological Sciences; Cardiac output; Cardiomyopathies; Cardiomyopathy, Dilated - drug therapy; Cardiomyopathy, Dilated - physiopathology; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Disease Models, Animal; Echocardiography; Heart; Inurement; Mice; Mice, Transgenic; Myocardium - enzymology; Phenotypes; Receptors; Survival analysis; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.091102398

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.