The hormone relaxin (RLN) exerts vasodilatory, anti-fibrotic, anti-apoptotic and anti-inflammatory as well as positive inotropic effects in the cardiovascular system. However, recombinant RLN could not improve long-term outcomes in the RELAX-AHF-studies. A potential explanation lies in the absence of its cognate receptor, Relaxin-receptor 1 (RXFP1), in ventricular cardiomyocytes. Based on this hypothesis, transgenic mice with a cardiomyocyte specific RXFP1 overexpression were generated. These transgenics were used to examine safety of the genetic modification as well as protective effects in a model of pressure-overload induced heart failure (HF) and the role of endogenous RLN for receptor activation. 

 

Transgenic mice with a cardiomyocyte specific overexpression of human RXFP1 (RXFP1tg) were generated. The extent of RXFP1 expression ranged from levels achievable by gene therapy to a 170-fold higher overexpression. Even in RXFP1tg with high levels of overexpression, no differences in phenotype and baseline cardiac function compared to wildtype (WT) mice were detected.

Receptor functionality was demonstrated by in-vivo pressure-loop experiments. Administration of recombinant RLN could induce positive inotropy only in RXFP1tg mice. An increase in phospholamban-phosphorylation at serine 16 was identified as a molecular correlate. 

To evaluate cardioprotective RXFP1 effects, RXFP1tg and WT control mice were subjected to transverse aortic constriction (TAC). RXFP1tg were protected from TAC-induced pressure overload, presenting not only an attenuated decline in systolic left ventricular (LV) function but also significantly less LV dilation compared to WT mice. In addition, pulmonary congestion seen in WT mice was attenuated in RXFP1tg. Molecularly, transgenic hearts showed significantly less activation of the fetal gene program as well as lower expression levels of fibrosis markers.

These protective effects correlate with the level of RXFP1 overexpression and were evident in both sexes. This suggests RXFP1 overexpression as a potential therapeutic approach for HF therapy. 

 

Cardiomyocyte specific RXFP1 overexpression protects dose dependently from TAC-induced heart failure even without exogenous RLN supplementation. Thus, cardiac RXFP1 overexpression presents a novel therapeutic approach providing baseline protection with optional specific activation by RLN supplementation.