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Intravenous delivery of AAV9 encoding urocortin 2 increases cardiac function in normal mice
Author(s) -
Lai N. Chin,
Hammond H. Kirk,
Tang Tong,
Guo Tracy,
Tang Rouying,
Parikh Jay,
Gao Meihua
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1134.1
Subject(s) - urocortin , adeno associated virus , ventricle , medicine , cardiac function curve , genetic enhancement , heart failure , biology , gene delivery , endocrinology , cardiology , gene , receptor , vector (molecular biology) , genetics , recombinant dna
Gene transfer for the treatment of cardiovascular diseases is conceptually attractive, but difficulty in obtaining high yield expression in the heart in a manner that can be easily and safely applied has been an impediment to progress. In this study, we tested the efficacy of an adeno‐associated virus 9 (AAV9) vector encoding urocortin 2 (Ucn2), which is a vasoactive peptide in the corticotropin‐releasing factor family that has beneficial effects in animals and patients with heart failure. AAV9.Ucn2 (5×10 11 genome copies) was delivered by intravenous injection. Four weeks after gene transfer, AAV9 vector DNA (qPCR) was increased by 115,854‐fold and Ucn2 mRNA by 10,523‐fold in liver vs control. Ucn2 DNA and mRNA were increased 15‐ and 34‐fold, respectively, in the left ventricle (LV). Also seen were increases in: plasma Ucn2, LV +dP/dt, LV −dP/dt, and LV developed pressure (Table). Conclusion Intravenous delivery of AAV9.Ucn2 provides sustained increases in serum Ucn2 and LV contractile function, indicating a potential role for paracrine‐based gene transfer for the treatment of heart failure.Control AAV9.Ucn2 Fold Δ *Liver AAV9 DNA (copies/ng) 0.26±0.05 3×10 5 ±3906 115,854 Liver Ucn2 mRNA (relative copies) 166±17 17×10 5 ±15×10 4 10,523 LV AAV9 DNA (copies/ng) 18±6 301±45 15 LV Ucn2 mRNA (relative copies) 34±9 958±299 34 Plasma Ucn2 (ng/ml) 2.6±0.1 6.0 ±0.3 2.3 LV +dP/dt (mmHg/s) 4,103±335 6,115±334 1.5 LV −dP/dt (mmHg/s) 3,744±335 5,631±365 1.5 LV Pressure (mmHg) 70±3 88±3 1.3 Heart Rate (beats/min) 439±9 420±14 0.9Control (n=14); AAV9.Ucn2 (n=9); except DNA: (n=9, ea group) & plasma Unc2 (n=4 ea group);* p <0.05 to <0.001, except for heart rate