Urocortin 2 Gene Transfer Improves Heart Function in Aged Mice

Mol Ther. 2020 Jan 8;28(1):180-188. doi: 10.1016/j.ymthe.2019.10.003. Epub 2019 Oct 29.

Abstract

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.

Keywords: AAV; HFpEF; LV strain; age-related LV dysfunction; contractile function; diastolic function; gene transfer; urocortin 2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging*
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Corticotropin-Releasing Hormone / blood
  • Corticotropin-Releasing Hormone / genetics*
  • Female
  • Gene Transfer Techniques*
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Stroke Volume
  • Urocortins / blood
  • Urocortins / genetics*
  • Ventricular Dysfunction, Left / prevention & control*
  • Ventricular Dysfunction, Left / therapy*
  • Ventricular Function, Left / genetics

Substances

  • Urocortins
  • urocortin 2, mouse
  • Corticotropin-Releasing Hormone
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Atp2a2 protein, mouse