Article

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.

Download full-text

Full-text

Available from: Chrishan S Samuel, Jul 24, 2014
1 Follower
 · 
170 Views
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    ABSTRACT: Renal dysfunction is a frequent finding in patients with acute heart failure (AHF) and an important prognostic factor for adverse outcomes. Worsening of renal function occurs in 30-50 % of patients hospitalised for AHF, and is associated with increased mortality, prolonged hospital stay and increased risk of readmission. Likely mechanisms involved in the decrease in renal function include impaired haemodynamics and activation of neurohormonal factors, such as the renin-angiotensin-aldosterone system, the sympathetic nervous system and the arginine-vasopressin system. Additionally, many drugs currently used to treat AHF have a detrimental effect on renal function. Therefore, pharmacotherapy for AHF should carefully take into account any potential complications related to renal function. Serelaxin, currently in clinical development for the treatment of AHF is a recombinant form of human relaxin-2, identical in structure to the naturally occurring human relaxin-2 peptide hormone that mediates cardiac and renal adaptations during pregnancy. Data from both pre-clinical and clinical studies indicate a potentially beneficial effect of serelaxin on kidney function. In this review, we discuss the mechanisms and impact of impairment of renal function in AHF, and the potential benefits of new therapies, such as serelaxin, in this context.
    Clinical Research in Cardiology 03/2015; DOI:10.1007/s00392-015-0839-y · 4.17 Impact Factor