Intravenous adeno-associated virus serotype 8 encoding urocortin-2 provides sustained augmentation of left ventricular function in mice.
Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. Here we ask whether a single intravenous injection of adeno-associated virus type 8 encoding murine urocortin-2 (AAV8.UCn2) could provide long-term elevation in plasma UCn2 levels and increased left ventricular (LV) function. Normal mice received AAV8.UCn2 (5×10¹¹ genome copies, intravenous). Plasma UCn2 increased 15-fold 6 weeks and >11-fold 7 months after delivery. AAV8 DNA and UCn2 mRNA expression was persistent in LV and liver up to 7 months after a single intravenous injection of AAV8.UCn2. Physiological studies conducted both in situ and ex vivo showed increases in LV +dP/dt and in LV -dP/dt, findings that endured unchanged for 7 months. SERCA2a mRNA and protein expression was increased in LV samples and Ca²⁺ transient studies showed an increased rate of Ca²⁺ decline in cardiac myocytes from mice that had received UCn2 gene transfer. We conclude that a single intravenous injection of AAV8.UCn2 increases plasma UCn2 and increases LV systolic and diastolic function for at least 7 months. The simplicity of intravenous injection of a long-term expression vector encoding a gene with paracrine activity to increase cardiac function is a potentially attractive strategy in clinical settings. Future studies will determine the usefulness of this approach in the treatment of heart failure.
VA San Diego Healthcare System, San Diego, CA 92161, USA.
Mei Hua
MH
Gao
N Chin
NC
Lai
Atsushi
A
Miyanohara
Jan M
JM
Schilling
Jorge
J
Suarez
Tong
T
Tang
Tracy
T
Guo
Ruoying
R
Tang
Jay
J
Parikh
Dimosthenis
D
Giamouridis
Wolfgang H
WH
Dillmann
Hemal H
HH
Patel
David M
DM
Roth
Nancy D
ND
Dalton
H Kirk
HK
Hammond
D000818:Animals; D002118:Calcium; D003346:Corticotropin-Releasing Hormone / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006333:Heart Failure / Q000628:therapy*; D006352:Heart Ventricles / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics; D054832:Urocortins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016277:Ventricular Function, Left / Q000235:genetics*
D012333:RNA, Messenger; D054832:Urocortins; C518358:urocortin 2, mouse; D003346:Corticotropin-Releasing Hormone; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D002118:Calcium