Urocortin 3 Gene Transfer Increases Function of the Failing Murine Heart

Background. Peptide infusions of the corticotropin releasing factor family, including urocortin 2, stresscopin, and urocortin 3 (UCn3) have favorable acute effects in clinical heart failure (HF), but their short half-lives make them unsuited for chronic therapy. Here we ask whether UCn3 gene transfer, which provides sustained elevation of plasma UCn3 levels, increases function of the failing heart. Methods. HF was induced by transmural left ventricular (LV) cryoinjury in mice. LV function was assessed 3 weeks later by echocardiography; those with ejection fractions (EF) <40% received intravenous (IV) saline, or IV adeno-associated virus type-8 encoding murine UCn3 (AAV8.mUCn3; 1.9x1013 genome copies (gc)/kg). Five weeks after randomization, repeat echocardiography, assessment of LV function (+dP/dt, -dP/dt), and quantification of Ca2+ transients and sarcomere shortening in isolated cardiac myocytes were conducted, and assessment of LV Ca2+ handling and stress proteins was performed. Results. Three weeks after MI, prior to treatment, EFs were reduced (mean 31%, from 63% in sham-operated animals). Mice randomized to receive UCn3 gene transfer (GT) showed increased plasma UCn3 (from 0.1±.01 ng/mL in saline group to 5.6±1.1 ng/mL; n=12 each group; p<.0001). Compared to mice that received saline, UCn3 gene transfer was associated with higher values for: EF (p=.0006); LV +dP/dt (p<.0001) and LV -dP/dt (p<.0001). Cardiac myocytes from mice that received UCn3 gene transfer showed higher peak Ca2+ transients (p=.0005), lower time constant of cytosolic Ca2+ decline (Tau, p<.0001), and higher rates of sarcomere shortening (+dL/dt, p=.03) and lengthening (- dL/dt, p=.04). LV samples from mice that received UCn3 gene transfer contained higher levels of SERCA2a (p=.0004 vs HF) and increased amounts of phosphorylated troponin I (p=.04 vs HF). Conclusion. UCn3 gene transfer is associated with improved Ca2+ handling and LV function in mice with HF and reduced EF.