Intravenous adeno-associated virus serotype 8 encoding urocortin-2 provides sustained augmentation of left ventricular function in mice

Hum Gene Ther. 2013 Sep;24(9):777-85. doi: 10.1089/hum.2013.088.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium
  • Corticotropin-Releasing Hormone / blood
  • Corticotropin-Releasing Hormone / genetics*
  • Corticotropin-Releasing Hormone / metabolism
  • Dependovirus / genetics*
  • Gene Transfer Techniques
  • Genetic Therapy / methods*
  • Genetic Vectors / genetics
  • Heart Failure / therapy*
  • Heart Ventricles / metabolism
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / metabolism
  • RNA, Messenger / biosynthesis
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / biosynthesis
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Urocortins / blood
  • Urocortins / genetics*
  • Urocortins / metabolism
  • Ventricular Function, Left / genetics*


  • RNA, Messenger
  • Urocortins
  • urocortin 2, mouse
  • Corticotropin-Releasing Hormone
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Atp2a2 protein, mouse
  • Calcium