title: Intravenous AAV8 Encoding Urocortin-2 Increases Function of the Failing Heart in Mice.
abstract: Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, is costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. We previously showed that a single intravenous (IV) injection of AAV8.UCn2 increases plasma UCn2 and left ventricular (LV) systolic and diastolic function for at least 7 months in normal mice. Here we test the hypothesis that IV delivery of AAV8.UCn2 increases function of the failing heart. Myocardial infarction (MI, by coronary ligation) was used to induce heart failure, which was assessed by echocardiography 3 weeks after MI. Mice with LV ejection fraction (EF) <25% received IV delivery of AAV8.UCn2 (5×10(11) gc) or saline, and 5 weeks later echocardiography showed increased LV EF in mice that received UCn2 gene transfer (p=0.01). In vivo physiological studies showed a 2-fold increase in peak rate of LV pressure development (LV +dP/dt; p<0.0001) and a 1.6-fold increase in peak rate of LV pressure decay (LV -dP/dt; p=0.0007), indicating increased LV systolic and diastolic function in treated mice. UCn2 gene transfer was associated with increased peak systolic Ca(2+) transient amplitude and rate of Ca(2+) decline and increased SERCA2a expression. In addition, UCn2 gene transfer reduced Thr286 phosphorylation of Cam kinase II, and increased expression of cardiac myosin light chain kinase, findings that would be anticipated to increase function of the failing heart. We conclude that a single IV injection of AAV8.UCn2 increases function of the failing heart. The simplicity of IV injection of a vector encoding a gene with beneficial paracrine effects to increase cardiac function is an attractive potential clinical strategy.
authors.affiliation: 1 VA San Diego Healthcare System , San Diego, CA 92161.|2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: N Chin
authors.initials: NC
authors.lastname: Lai
authors.affiliation: 1 VA San Diego Healthcare System , San Diego, CA 92161.|2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Gao
authors.affiliation: 1 VA San Diego Healthcare System , San Diego, CA 92161.|2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: Dimosthenis
authors.initials: D
authors.lastname: Giamouridis
authors.affiliation: 2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: Jorge
authors.initials: J
authors.lastname: Suarez
authors.affiliation: 2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyanohara
authors.affiliation: 1 VA San Diego Healthcare System , San Diego, CA 92161.|2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: Jay
authors.initials: J
authors.lastname: Parikh
authors.affiliation: 1 VA San Diego Healthcare System , San Diego, CA 92161.|2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hightower
authors.affiliation: 2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: Tracy
authors.initials: T
authors.lastname: Guo
authors.affiliation: 2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dillmann
authors.affiliation: 2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: 2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: Julieta
authors.initials: J
authors.lastname: Diaz-Juarez
authors.affiliation: 1 VA San Diego Healthcare System , San Diego, CA 92161.|2 Department of Medicine, University of California-San Diego , San Diego, CA 92161.
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004562:Electrocardiography; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D006339:Heart Rate / Q000235:genetics; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D054832:Urocortins / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D016277:Ventricular Function, Left / Q000235:genetics
chemical_list: D054832:Urocortins; C518358:urocortin 2, mouse; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium