Urocortin 2Gene Transfer Improves Heart Function in Aged Mice

Prevalence of left ventricular (LV) systolic and diastolic dysfunction increases with aging. We previously reported that urocortin 2(Ucn2) gene transfer increases heart function in mice with heart failure with reduced ejection fraction. Here, we test the hypotheses that (1) Ucn2gene transfer will increase LV function in aged mice and that (2) Ucn2gene transfer given in early life will prevent age-related LV dysfunction. Nineteen-month-old (treatment study) and 3-month-old (prevention study) mice received Ucn2gene transfer or saline. LV function was examined 3–4 months (treatment study) or 20 months (prevention study) after Ucn2gene transfer or saline injection. In both the treatment and prevention strategies, Ucn2gene transfer increased ejection fraction, reduced LV volume, increased LV peak −dP/dt and peak +dP/dt, and reduced global longitudinal strain. Ucn2gene transfer—in both treatment and prevention strategies—was associated with higher levels of LV SERCA2a protein, reduced phosphorylation of LV CaMKIIa, and reduced LV α-skeletal actin mRNA expression (reflecting reduced cardiac stress). In conclusion, Ucn2gene transfer restores normal cardiac function in mice with age-related LV dysfunction and prevents development of LV dysfunction.