Urocortin 2 Gene Transfer Improves Heart Function in Aged Mice

• Published in: Molecular therapy Vol. 28; no. 1; pp. 180 - 188
• Main Authors: Giamouridis, Dimosthenis, Gao, Mei Hua, Lai, N. Chin, Guo, Tracy, Miyanohara, Atsushi, Blankesteijn, W. Matthijs, Biessen, Erik A.L., Hammond, H. Kirk
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-01-2020; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: AAV; Actin; Age; age-related LV dysfunction; Aging; Animals; Ca2+-transporting ATPase; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Congestive heart failure; contractile function; Corticotropin-Releasing Hormone - blood; Corticotropin-Releasing Hormone - genetics; diastolic function; Female; Gene transfer; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Heart rate; HEK293 Cells; HFpEF; Humans; Kinases; LV strain; Male; Mice; Mice, Inbred C57BL; Original; Peptides; Phosphorylation; Plasma; Prevention; Protein expression; Proteins; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Stroke Volume; Studies; Urocortin; urocortin 2; Urocortins - blood; Urocortins - genetics; Ventricle; Ventricular Dysfunction, Left - prevention & control; Ventricular Dysfunction, Left - therapy; Ventricular Function, Left - genetics; contractile function; gene transfer; diastolic function; AAV; LV strain; age-related LV dysfunction; HFpEF; urocortin 2
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.10.003

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) Ucn2 gene transfer will increase LV function in aged mice and that (2) Ucn2 gene transfer given in early life will prevent age-related LV dysfunction. Nineteen-month-old (treatment study) and 3-month-old (prevention study) mice received Ucn2 gene transfer or saline. LV function was examined 3–4 months (treatment study) or 20 months (prevention study) after Ucn2 gene transfer or saline injection. In both the treatment and prevention strategies, Ucn2 gene transfer increased ejection fraction, reduced LV volume, increased LV peak −dP/dt and peak +dP/dt, and reduced global longitudinal strain. Ucn2 gene 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, Ucn2 gene transfer restores normal cardiac function in mice with age-related LV dysfunction and prevents development of LV dysfunction.
We show that urocortin 2 gene transfer corrects age-related LV dysfunction, demonstrating the potential therapeutic benefit of urocortin 2 gene transfer in a preclinical model of HFpEF. In addition, a single intravenous injection of the vector provides a sustained increase in plasma urocortin 2 and prevents development of age-related LV dysfunction.
[Display omitted]