Protective RXFP1 Properties in Distinct Murine Heart Failure Models

Objective:
Despite numerous diagnostic and therapeutic innovations over the last decade, heart failure (HF) remains associated with high morbidity and mortality and thus demands novel therapeutic approaches. The Relaxin Family Peptide Receptor 1 (RXFP1) and its associated ligand Relaxin (RLX) are known for their pleiotropic signaling pathways and protective effects in various organs. Cardiac RXFP1 signaling has been shown to exert positive inotropic, anti-hypertrophic, anti-ischemic, anti-inflammatory, anti-fibrotic and pro-angiogenic effects. This makes RXFP1 a promising therapeutic target for HF. The aim of the present study was to explore the potential utility of RXFP1 overexpression in different murine HF phenotypes.

Methods and Results:   
RXFP1 expression is limited to the atria in humans and mice. To explore its protective potential in ventricular diseases, we assessed a transgenic mouse line (TG) with cardiomyocyte-specific RXFP1 overexpression and compared it to wild-type (WT) mice in models of transversal aortic constriction (TAC), chronic Angiotensin II infusion (ANGII), and permanent ligation of the left anterior coronary (LAD-MI). Cardiac function and remodeling were assessed via echocardiography, and tissues were analyzed for RNA, protein, and fibrosis. 4 weeks of ANGII increased mean arterial pressure (MAP), left ventricular (LV) hypertrophy, fibrosis, lung congestion, and cardiac remodeling, causing HFpEF phenotype with impaired diastolic but preserved systolic function. TG mice had similarly high MAP but preserved diastolic function, less LV hypertrophy and fibrosis, no pulmonary congestion, and normalized cardiac remodeling. Permanent LAD ligation reduced cardiac function in both WT and TG mice, with no significant differences in cardiac function, infarct size, or post-MI troponin T. RLX infusion for 2 weeks did not improve cardiac function or remodeling. TAC Model: TAC surgery reduced cardiac function, caused LV hypertrophy and fibrosis, and activated cardiac remodeling. TG mice had attenuated cardiac dysfunction, preserved LV geometry, and normalized hypertrophy and fibrosis.

Conclusion:
We studied cardiomyocyte-specific RXFP1 overexpression in distinct HF phenotype: ANGII infusion, permanent LAD ligation, and TAC. RXFP1 expression preserved cardiac function, reduced LV hypertrophy and fibrosis, and normalized remodeling markers in two models. However, it had no significant effect on cardiac function or remodeling in ischemic HF, likely due to its limited impact on scar formation. These findings underscore the benefits of RXFP1 expression in HF phenotypes of fibrosis and hypertrophy.