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Urocortin‐3 Gene Transfer Increases Function of the Failing Heart in Mice
Author(s) -
Giamouridis Dimosthenis,
Lai Ngai Chin,
Gao Meihua,
Blankesteijn Matthijs,
Biessen Erik,
Hammond H Kirk
Publication year - 2017
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.31.1_supplement.687.13
Subject(s) - heart failure , urocortin , medicine , ejection fraction , cardiac function curve , adeno associated virus , saline , genetic enhancement , cardiology , endocrinology , gene , receptor , biology , recombinant dna , biochemistry , vector (molecular biology)
Urocortin 3 (UCn3), a member of the corticotropin releasing factor family, has beneficial effects on cardiac function. Long term therapy using this peptide is encumbered by its short half‐life, ~5 minutes, which can be resolved by gene transfer. We have shown that heart function was increased by a single intravenous (IV) injection of an adeno‐associated virus 8 encoding UCn2 (AAV8.UCn2) or UCn3 (AAV8.UCn3) in normal mice. Furthermore, UCn2 gene transfer (GT) ameliorated function of the failing mouse heart. In the current study, we explore the effects of UCn3 gene transfer in heart failure. Our hypothesis was that UCn3 gene transfer would increase function of the failing heart in mice. Heart failure was induced by cryoinjury in 10w‐old C57Bl/6 male mice. Three weeks later heart function was assessed by echocardiography and mice with ejection fraction (EF) <40% were randomly assigned to receive IV saline (control), or IV AAV8.UCn3 (5×10 11 gc/mouse). Five weeks after randomization, mice that received UCn3 GT had increased EF (UCn3 GT: Pre, 29 ± 2%; Post, 36 ± 2%; n=7; p=0.0072; Saline: Pre, 30 ± 2%; Post, 28 ± 2%; n=6; p=0.44; saline‐post vs UCn3 GT‐post, p=0.015). Hemodynamic assessment of left ventricular (LV) function using a Millar conductance micromanometer catheter showed that UCn3 GT was associated with increased rate of LV peak pressure development (+dP/dt) (UCn3: 7288 ± 586 mmHg/s, n=7; Saline: 4112 ± 309 mmHg/sec, n=5; p=0.0017) and decay (−dP/dt) (UCn3: −6457 ± 303 mmHg/s, n=7; Saline: −4302 ± 249 mmHg/s, n=5; p=0.0004). There was no group difference in heart rate. In conclusion, UCn3 gene transfer increases function of the failing heart. This study demonstrates the potential of UCn3 GT as a therapeutic intervention for patients with heart failure. Support or Funding Information NIH grant P01 HL66941A. Ejection fraction (EF) before and 5 weeks after treatment in mice with heart failure (HF). B. LV peak pressure development (+dP/dt); C. LV peak pressure decay (−dP/dt); D. Heart rate (HR); bpm, beats per minute; Mean and standard errors are shown; p values from Student's t‐test.