Abstract 14324: Effects of Exogenous Relaxin in Aldosterone-mediated Cardiac Fibrosis in Heart Failure
Background: Serelaxin (RLX), a recombinant form of human relaxin 2, is a vasoactive hormone with interesting endocrine/paracrine properties on cardiovascular system. Relaxin is clinically explored in acute heart failure. In this context, this work aimed to explore the effects of a prolonged administration of RLX in a murine model of chronic heart failure involving myocardial alterations due to association of isoproterenol and aldosterone.
Methods: Three month-old male WT and AS (transgenic overexpressing cardiac aldosterone synthase) FVB mice were pretreated for 48 hours with isoproterenol (ISO; 2 injections/day, 150 mg/kg/injection) to induce a systolic heart failure. RLX (24 μg/day) was given for 28 days by osmotic minipumps to WT and AS mice. These groups were compared to RLX-untreated control mice.
Results: ISO-treated AS mice developed cardiac hypertrophy (HW/TL: 9.4%, p<0.05) with systolic dysfunction (SF decreased from 44% to 36%, p<0.01) that lasted for 28 days, and an important myocardial fibrosis at day 31 (+300% vs AS controls, p<0.01). Compared to RLX-untreated AS ISO-treated mice, RLX enabled an improvement in shortening fraction (SF) (p<0.01 to days 10, 17, 24 and 31, 44% vs 38% at day 31), attenuation of myocardial fibrosis at day 31 (-46%, p<0.01), decreased mRNA overexpression of MCP 1 (-60%, p<0.05) and restoration of altered expression of the pro-angiogenic VEGFA and anti-fibrotic MMP 9 transcripts at levels comparable to control AS mice at day 31. The WT mice developed a transient systolic dysfunction after ISO. RLX allowed a faster recovery of their SF at day 10 (41% versus 38%, p<0.05) and reduced the overexpression of ANP at day 31 (-38%, p<0.05) but had no effect on myocardial fibrosis at day 31. The altered NOS 3 expression was however not improved by RLX in both AS and WT mice (p> 0.05).
Conclusion: Our results show a beneficial effect of a 28 day RLX treatment on systolic cardiac dysfunction induced by isoproterenol and overexpression of cardiac aldosterone in mice with an improvement of cardiac function and anti-fibrotic, anti-inflammatory, and proangiogenic actions. These results suggest that RLX could be used as background therapy of chronic heart failure, provided that further evaluation be done.
Author Disclosures: G. Billebeau: None. G. Vergaro: None. M. Prudhomme: None. R. Merval: None. E. Polidano: None. A. Cohen Solal: None. C. Delcayre: None.
- © 2016 by American Heart Association, Inc.