Cardiovascular effects of relaxin: From basic science to clinical therapy

Experimental Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Vic 3008, Australia.
Nature Reviews Cardiology (Impact Factor: 9.18). 11/2009; 7(1):48-58. DOI: 10.1038/nrcardio.2009.198
Source: PubMed


Although substantial advances have been achieved in recent decades in the clinical management of heart diseases, new therapies that provide better or additional efficacy with minimal adverse effects are urgently required. Evidence that has accumulated since the 1990s indicates that the peptide hormone relaxin has multiple beneficial actions in the cardiovascular system under pathological conditions and, therefore, holds promise as a novel therapeutic intervention. Clinical trials for heart failure therapy using relaxin revealed several beneficial actions. Here we review findings from mechanistic and applied research in this field, comment on the outcomes of recent phase I/II clinical trails on patients with heart failure, and highlight settings of cardiovascular diseases where relaxin might be effective.

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Available from: Chrishan S Samuel, Jul 24, 2014
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    • "Its native G-protein-coupled receptor, relaxin family peptide receptor 1 [5], RXFP1 (previously known as LGR7), was shown to be widely distributed in various organs in both males and females. Human (H2) relaxin, the major stored and circulating form of human relaxin, is now known to play a key role in inflammatory and matrix remodeling processes and possesses potent vasodilatory , angiogenic, and other cardioprotective actions [6] [7]. At physiological concentrations, the H2 relaxin exists as a monomer [3]. "
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    ABSTRACT: Human (H2) relaxin is a two-chain peptide member of the insulin superfamily and possesses potent pleiotropic roles including regulation of connective tissue remodeling and systemic and renal vasodilation. These effects are mediated through interaction with its cognate G-protein-coupled receptor, RXFP1. H2 relaxin recently passed Phase III clinical trials for the treatment of congestive heart failure. However, its in vivo half-life is short due to its susceptibility to proteolytic degradation and renal clearance. To increase its residence time, a covalent dimer of H2 relaxin was designed and assembled through solid phase synthesis of the two chains, including a judiciously monoalkyne sited B-chain, followed by their combination through regioselective disulfide bond formation. Use of a bisazido PEG 7 linker and " click " chemistry afforded a dimeric H2 relaxin with its active site structurally unhindered. The resulting peptide possessed a similar secondary structure to the native monomeric H2 relaxin and bound to and activated RXFP1 equally well. It had fewer propensities to activate RXFP2, the receptor for the related insulin-like peptide 3. In human serum, the dimer had a modestly increased half-life compared to the monomeric H2 relaxin suggesting that additional oligomerization may be a viable strategy for producing longer acting variants of H2 relaxin.
    Full-text · Article · Jan 2015 · BioMed Research International
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    • "For example, serelaxin has been found to have a number of anti-inflammatory effects, including reducing inflammatory cell infiltration into myocardial tissue following ischemia [58]. In addition, serelaxin promotes cell survival by reducing oxidative stress-mediated apoptosis, calcium overload, and infarct size in animal models of ischemia/reperfusion injury (Fig. 3) [33, 58]. By stimulating angiogenesis, and improving stem cell survival and cell–cell coupling, serelaxin may also facilitate myocardial tissue healing [33]. "
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    ABSTRACT: Acute heart failure (AHF) is characterized by high morbidity and mortality and high costs. Although the treatment of AHF has not changed substantially in recent decades, it is becoming clear that treatment strategies for AHF need to address both the immediate hemodynamic abnormalities giving rise to congestion as well as prevent organ damage that can influence long-term prognosis. Serelaxin, the recombinant form of human relaxin-2, a naturally occurring peptide hormone, has been found to significantly improve symptoms and signs of AHF, prevent in-hospital worsening heart failure, as well as significantly improve 180-day cardiovascular and all-cause mortality after a 48-h infusion commenced within 16 h of presentation (RELAX-AHF study). Available data suggest that the clinical benefits may be attributable to a potential combination of multiple actions of serelaxin, including improving systemic, cardiac, and renal hemodynamics, and protecting cells and organs from damage via anti-inflammatory, anti-cell death, anti-fibrotic, anti-hypertrophic, and pro-angiogenic effects. This manuscript describes the short- and long-term effects of serelaxin in AHF patients, analyzing how these effects can be explained by taking into account the range of hemodynamic and non-hemodynamic actions of serelaxin. In addition, this paper also addresses several aspects related to the role of serelaxin in the therapy of AHF that remain to be clarified and warrant further investigation.
    Preview · Article · Mar 2014 · American Journal of Cardiovascular Drugs
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    • "Relaxin displays no cross-reactivity for RXFP3 and RXFP4, the receptors for relaxin-3 and insulin-like peptide 5 (INSL5) (Shabanpoor et al., 2009). The cardio-protective effects of H2 relaxin are known to be mediated by RXFP1 (Du et al., 2010). Relaxin and RXFP1 are present in a number of different regions of the rat (Osheroff and Phillips, 1991; Ma and Gundlach, 2007) and mouse (Piccenna et al., 2005) brain, but their role there has not been clearly identified. "
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    ABSTRACT: Relaxin, a heterodimeric polypeptide hormone, is a key regulator of collagen metabolism and multiple vascular control pathways in humans and rodents. Its actions are mediated via its cognate G-protein-coupled receptor, RXFP1 although it also "pharmacologically" activates RXFP2, the receptor for the related, insulin-like peptide 3 (INSL3), which has specific actions on reproduction and bone metabolism. Therefore, experimental tools to facilitate insights into the distinct biological actions of relaxin and INSL3 are required, particularly for studies of tissues containing both RXFP1 and RXFP2. Here, we chemically functionalized human (H2) relaxin, the RXFP1-selective relaxin analog H2:A(4-24)(F23A), and INSL3 to accommodate a fluorophore without marked reduction in binding or activation propensity. Chemical synthesis of the two chains for each peptide was followed by sequential regioselective formation of their three disulfide bonds. Click chemistry conjugation of Cy5.5 at the B-chain N-terminus, with conservation of the disulfide bonds, yielded analogs displaying appropriate selective binding affinity and ability to activate RXFP1 and/or RXFP2 in vitro. The in vivo biological activity of Cy5.5-H2 relaxin and Cy5.5-H2:A(4-24)(F23A) was confirmed in mice, as acute intracerebroventricular (icv) infusion of these peptides (but not Cy5.5-INSL3) stimulated water drinking, an established behavioral response elicited by central RXFP1 activation. The central distribution of Cy5.5-conjugated peptides was examined in mice killed 30 min after infusion, revealing higher fluorescence within brain tissue near-adjacent to the cerebral ventricle walls relative to deeper brain areas. Production of fluorophore-conjugated relaxin family peptides will facilitate future pharmacological studies to probe the function of H2 relaxin/RXFP1 and INSL3/RXFP2 signaling in vivo while tracking their distribution following central or peripheral administration.
    Full-text · Article · Dec 2013 · Frontiers in Chemistry
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