Recombinant Fc-Elabela fusion protein has extended plasma half-life andmitigates post-infarct heart dysfunction in rats

Activation of the apelin receptor, or APJ, by apelin is considered a therapeutic avenue for cardiovascular disease, including heart failure. Recently, a novel endogenous ligand for APJ named Elabela (ELA) has been discovered and is known to possess anti-heart failure activity in animal models. However, the short in vivo half-life of ELA constrains its clinical potential. To extend its half-life in vivo, we attempted to make IgG-Fc-ELA fusion proteins. We found that Fc-ELA-32 fusion proteins are cleaved during protein production, whereas Fc-ELA-21 fusion proteins are expressed intact, so we focused our studies on the latter. The Fc-ELA-21 fusion protein retained its functionality in vitro and had a half-life of approximately 44 h in circulation in mice after subcutaneous injection. Daily injection of the fusion protein in MI rats for 4 weeks significantly mitigated heart dysfunction with respect to hemodynamics. At the cellular and tissue levels, treatment of Fc-ELA-21 fusion protein significantly increased angiogenesis, promoted cardiomyocyte proliferation and reduced apoptosis and heart fibrosis near the infarct area. In comparison, ELA-21 had a half-life of 13 min and showed no significant cardioprotective activities. These data suggest that Fc-ELA-21 may be a potential therapeutic for heart failure.