Preservation of Myocardial β -Adrenergic Receptor Signaling Delays the Development of Heart Failure after Myocardial Infarction

• Published in: Proceedings of the National Academy of Sciences - PNAS 2000-05, Vol.97 (10), p.5428-5433
• Main Authors: White, David C., Hata, Jonathan A., Shah, Ashish S., Glower, Donald D., Lefkowitz, Robert J., Koch, Walter J.
• Format: Article
• Language: English
• Subjects: Adenoviridae; Adenylyl Cyclases - metabolism; Animals; Animals, Genetically Modified; b-adrenergic receptor kinase; b-adrenergic receptors; beta-Adrenergic Receptor Kinases; Biochemistry; Biological Sciences; Blood Pressure; Catecholamines; Cell Membrane - enzymology; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Down regulation; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Heart; Heart attacks; Heart failure; Heart Failure - prevention & control; Heart Rate; Hemodynamics; Humans; Inurement; Leporidae; Ligation; Male; Medical research; Myocardial Infarction - complications; Myocardial Infarction - physiopathology; Myocardium; Myocardium - metabolism; Rabbits; Receptors; Receptors, Adrenergic, beta - physiology; Signal Transduction; Transgenes; Ventricular Function, Left
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.090091197

When the heart fails, there is often a constellation of biochemical alterations of the β -adrenergic receptor (β AR) signaling system, leading to the loss of cardiac inotropic reserve. β AR down-regulation and functional uncoupling are mediated through enhanced activity of the β AR kinase (β ARK1), the expression of which is increased in ischemic and failing myocardium. These changes are widely viewed as representing an adaptive mechanism, which protects the heart against chronic activation. In this study, we demonstrate, using in vivo intracoronary adenoviral-mediated gene delivery of a peptide inhibitor of β ARK1 (β ARKct), that the desensitization and down-regulation of β ARs seen in the failing heart may actually be maladaptive. In a rabbit model of heart failure induced by myocardial infarction, which recapitulates the biochemical β AR abnormalities seen in human heart failure, delivery of the β ARKct transgene at the time of myocardial infarction prevents the rise in β ARK1 activity and expression and thereby maintains β AR density and signaling at normal levels. Rather than leading to deleterious effects, cardiac function is improved, and the development of heart failure is delayed. These results appear to challenge the notion that dampening of β AR signaling in the failing heart is protective, and they may lead to novel therapeutic strategies to treat heart disease via inhibition of β ARK1 and preservation of myocardial β AR function.