https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; 2Universitätsklinikum Heidelberg Innere Medizin III, Inst. für Molekulare und Translationale Kardiologie Heidelberg, Deutschland; 3Universitätsklinikum Augsburg I. Medizinische Klinik Augsburg, Deutschland
Objective: Therapeutic options for heart failure with preserved ejection fraction (HFpEF) remain an urgent need in cardiovascular medicine. The human hormone Relaxin-H2 (RLN) exerts pleiotropic cardioprotective actions via its cognate receptor relaxin family peptide receptor 1 (RXFP1). Recent studies imply that RXFP1 could beneficially impact cardiac fibrosis, hypertrophy, and diastolic dysfunction. Thus, we aimed to investigate the effects and mechanisms of cardiac RXFP1 overexpression in an Angiotensin II (Ang II)-induced HFpEF in vivo model.
Methods and Results: Transgenic mice with cardiomyocyte-specific overexpression of RXFP1 (Tg(RXFP1)) and wild-type mice were treated with Ang II for 14 days (1.5 mg/kg/d) using subcutaneous osmotic mini-pumps. Serial echocardiography and left heart catheterization prior to sacrifice were performed for in vivo characterization. Although systolic function was fully maintained in Ang II-treated wild-type mice, these animals revealed ventricular hypertrophy and severe diastolic dysfunction while. In contrast, Tg(RXFP1) mice exposed to Ang II presented a preserved diastolic function, evidenced by normalized E/e’ ratio and reduced left ventricular end-diastolic pressure (LVEDP), as well as reduced relative lung weight, indicating decreased pulmonary congestion. Tg(RXFP1) mice further showed reduced heart to body weight ratio and cardiomyocyte cross-sectional area as well as reduced activation of the fetal gene program, indicating attenuated hypertrophy. Histological analysis of Tg(RXFP1) mice revealed decreased expression of collagens I, III, and VIII and diminished interstitial and perivascular fibrosis, another key driver of maladaptive remodeling in HFpEF. Additionally, single cell RNAseq and mass spectrometry data indicate that RXFP1 overexpression exerts its effects by modulation of extracellular matrix (ECM) and expression of cardiokines.
Conclusion: RXFP1 overexpression in cardiac tissue mitigates diastolic dysfunction and adverse remodeling in Ang II-induced HFpEF, with notable antifibrotic and antihypertrophic effects. These findings highlight RXFP1 signaling as a promising target for HFpEF therapy.