Targeting Myocardial β-Adrenergic Receptor Signaling and Calcium Cycling for Heart Failure Gene Therapy

• Published in: Journal of cardiac failure Vol. 13; no. 5; pp. 401 - 414
• Main Authors: Pleger, Sven T., MD, Boucher, Matthieu, PhD, Most, Patrick, MD, Koch, Walter J., PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2007
• Subjects: Animals; beta-Adrenergic Receptor Kinases - metabolism; beta-Adrenergic Receptor Kinases - physiology; Calcium - metabolism; Calcium - physiology; calcium regulation; Cardiomyopathy, Hypertrophic - physiopathology; Cardiomyopathy, Hypertrophic - therapy; Cardiovascular; Disease Models, Animal; G protein-coupled receptor kinase; G-Protein-Coupled Receptor Kinase 1 - blood; G-Protein-Coupled Receptor Kinase 1 - physiology; G-Protein-Coupled Receptor Kinase 2; gene therapy; Genetic Therapy; GTP-Binding Protein alpha Subunits - metabolism; heart failure; Heart Failure - metabolism; Heart Failure - physiopathology; Heart Failure - therapy; Humans; Myocardial Contraction - physiology; Myocardium - metabolism; Myocytes, Cardiac - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases; Receptors, Adrenergic, beta - genetics; Receptors, Adrenergic, beta - metabolism; Receptors, Adrenergic, beta - physiology; S100 Proteins - metabolism; S100A1; β-adrenergic receptors; G protein-coupled receptor kinase; heart failure; gene therapy; calcium regulation; S100A1; β-adrenergic receptors
• ISSN: 1071-9164; 1532-8414
• DOI: 10.1016/j.cardfail.2007.01.003

Abstract Heart failure (HF) is a leading cause of morbidity and mortality in Western countries and projections reveal that HF incidence in the coming years will rise significantly because of an aging population. Pharmacologic therapy has considerably improved HF treatment during the last 2 decades, but fails to rescue failing myocardium and to increase global cardiac function. Therefore, novel therapeutic approaches to target the underlying molecular defects of ventricular dysfunction and to increase the outcome of patients in HF are needed. Failing myocardium generally exhibits distinct changes in β-adrenergic receptor (βAR) signaling and intracellular Ca2+ -handling providing opportunities for research. Recent advances in transgenic and gene therapy techniques have presented novel therapeutic strategies to alter myocardial function and to target both βAR signaling and Ca2+ -cycling. In this review, we will discuss functional alterations of the βAR system and Ca2+ -handling in HF as well as corresponding therapeutic strategies. We will then focus on recent in vivo gene therapy strategies using the targeted inhibition of the βAR kinase (βARK1 or GRK2) and the restoration of S100A1 protein expression to support the injured heart and to reverse or prevent HF.