Effects of Urocortin 2 Versus Urocortin 3 Gene Transfer on Left Ventricular Function and Glucose Disposal

JACC Basic Transl Sci. 2018 May 30;3(2):249-264. doi: 10.1016/j.jacbts.2017.12.004. eCollection 2018 Apr.


UCn2 and UCn3 peptides have recently been infused to treat patients with heart failure (HF) but are limited by their short half-lives. A 1-time intravenous injection of virus vectors encoding UCn2 or UCn3 provided sustained increases in plasma concentrations of the peptides. This was associated with increases in both systolic and diastolic left ventricular (LV) function, mediated by increased LV SERCA2a expression and Ca2+ handling. UCn2, but not UCn3, gene transfer reduced fasting glucose and increased glucose disposal. These findings support UCn2 and UCn3 gene transfer as potential treatments for HF and indicate that UCn2 may be an optimal selection in patients with diabetes and HF.

Keywords: AAV, adeno-associated virus; CO, cardiac output; CRF, corticotropin-releasing factor; CRHR, corticotropin-releasing hormone receptor; CaMKII, Ca2+/calmodulin-dependent protein kinase II; EDD, end-diastolic diameter; EF, ejection fraction; ESD, end-systolic diameter; ESPVR, end-systolic pressure-volume relationship; HF, heart failure; IP, intraperitoneal; IV, intravenous; LV, left ventricle/ventricular; PKA, protein kinase A; RYR2, ryanodine receptor 2; SERCA2a, sarco/endoplasmic reticulum Ca2+-ATPase; Tau, time constant of left ventricular pressure decline; UCn2, urocortin 2; UCn3, urocortin 3; VCFc, velocity of circumferential fiber shortening corrected for heart rate; adeno-associated virus; cAMP, 3′,5′-cyclic adenosine monophosphate; contractile function; diastolic function; gc, genome copies; gene therapy; insulin sensitivity.