title: Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility.
abstract: Heart failure is characterized by depressed contractility and delayed repolarization. The latter feature predisposes the failing heart to ventricular arrhythmias and represents a logical target for gene therapy. Unfortunately, unopposed correction of the delay in repolarization will decrease the time available for calcium cycling during each heartbeat, potentially aggravating the depression of contractility. Here we describe the development and application of a novel gene therapy strategy designed to abbreviate excitation without depressing contraction. The calcium ATPase SERCA1 was coexpressed with the potassium channel Kir2.1 in guinea pig hearts. Myocytes from the hearts had bigger calcium transients and shorter action potentials. In vivo, repolarization was abbreviated, but contractile function remained unimpaired. Dual gene therapy of the sort described here can be generalized to exploit opposing or synergistic therapeutic principles to achieve a tailored phenotype.
authors.affiliation: Institute of Molecular Cardiobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Ennis
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Li
authors.forename: Anne M
authors.initials: AM
authors.lastname: Murphy
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
authors.forename: H Bradley
authors.initials: HB
authors.lastname: Nuss
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D020013:Calcium Signaling; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D004452:Echocardiography; D004562:Electrocardiography; D004594:Electrophysiology; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006168:Guinea Pigs; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases