Targeting myocardial beta-adrenergic receptor signaling and calcium cycling for heart failure gene therapy.
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 beta-adrenergic receptor (betaAR) 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 betaAR signaling and Ca2+-cycling. In this review, we will discuss functional alterations of the betaAR 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 betaAR kinase (betaARK1 or GRK2) and the restoration of S100A1 protein expression to support the injured heart and to reverse or prevent HF.
Pleger
Sven T
ST
George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Boucher
Matthieu
M
Most
Patrick
P
Koch
Walter J
WJ
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002312:Cardiomyopathy, Hypertrophic / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000097:blood / Q000502:physiology*; D054769:G-Protein-Coupled Receptor Kinase 2; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D015316:Genetic Therapy; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009418:S100 Proteins / Q000378:metabolism; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism / Q000502:physiology
D044385:GTP-Binding Protein alpha Subunits; D011943:Receptors, Adrenergic, beta; D009418:S100 Proteins; C110294:S100A1 protein; D017346:Protein Serine-Threonine Kinases; D051606:G-Protein-Coupled Receptor Kinase 1; C496567:GRK2 protein, human; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D002118:Calcium