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: 10.15). 11/2009; 7(1):48-58. DOI: 10.1038/nrcardio.2009.198
Source: PubMed

ABSTRACT 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.
    BioMed Research International 01/2015; 2015:Article ID 731852. DOI:10.1155/2015/731852 · 2.71 Impact Factor
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    • "In cardiovascular disease models, activation of endogenous RXFP1 in cardiac fibroblasts by relaxin results in important cardioprotective effects, including inhibition of hypertrophy and fibrosis (Du et al, 2010); thus this is an important model in which to study relaxin-stimulated signalling . Rat cardiac fibroblasts are poorly transfected, so it was necessary to infect the cells with an adenoviral version of the cytosolic Epac1-camps sensor (Ad-glEpac1; Nikolaev et al, 2005; Figure 1H and I). "
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    ABSTRACT: Biochemical studies suggest that G-protein-coupled receptors (GPCRs) achieve exquisite signalling specificity by forming selective complexes, termed signalosomes. Here, using cAMP biosensors in single cells, we uncover a pre-assembled, constitutively active GPCR signalosome, that couples the relaxin receptor, relaxin family peptide receptor 1 (RXFP1), to cAMP following receptor stimulation with sub-picomolar concentrations of peptide. The physiological effects of relaxin, a pleiotropic hormone with therapeutic potential in cancer metastasis and heart failure, are generally attributed to local production of the peptide, that occur in response to sub-micromolar concentrations. The highly sensitive signalosome identified here provides a regulatory mechanism for the extremely low levels of relaxin that circulate. The signalosome includes requisite Galpha(s), Gbetagamma and adenylyl cyclase 2 (AC2); AC2 is functionally coupled to RXFP1 through AKAP79 binding to helix 8 of the receptor; activation of AC2 is tonically opposed by protein kinase A (PKA)-activated PDE4D3, scaffolded through a beta-arrestin 2 interaction with Ser(704) of the receptor C-terminus. This elaborate, pre-assembled, ligand-independent GPCR signalosome represents a new paradigm in GPCR signalling and provides a mechanism for the distal actions of low circulating levels of relaxin.
    The EMBO Journal 08/2010; 29(16):2772-87. DOI:10.1038/emboj.2010.168 · 10.75 Impact Factor
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    ABSTRACT: Hypertension and aging are associated with large artery structural remodeling and stiffening, which are known to increase cardiovascular risk. Relaxin is a peptide hormone with potent antifibrotic action in multiple organs. Although relaxin is able to reduce peripheral vascular resistance and improve arterial compliance in rats, it remains unclear whether the improvement in compliance is indirectly attributed to a vasodilatory action or whether relaxin is able to reverse arterial remodeling and stiffening directly in aged hypertensive animals. Senescent spontaneously hypertensive rats (17 months old) were treated with relaxin for 2 weeks (0.5 mg/kg per day) followed by a 1-week washout period. We determined large artery compliance using in vivo and in vitro techniques and quantified arterial remodeling by morphological and chemical means. Relaxin therapy significantly reversed aortic remodeling (ie, increases in vessel size, wall thickness, and collagen content) and improved arterial compliance, effects independent of its vasodilatory action. In relaxin-treated spontaneously hypertensive rats, arterial collagen content showed a greater reduction (-31%; P<0.05) than that of elastin (-8%), resulting in an increased elastin:collagen ratio (0.63+/-0.03 versus 0.47+/-0.02; P<0.05). In conclusion, our results demonstrated that relaxin is potent in mediating reversal of arterial remodeling and improving arterial structural compliance in aged hypertensive rats.
    Hypertension 03/2010; 55(5):1260-6. DOI:10.1161/HYPERTENSIONAHA.109.149369 · 7.63 Impact Factor
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