The actions of relaxin on the human cardiovascular system

Abstract

The insulin-like peptide relaxin, originally identified as a hormone of pregnancy, is now known to exert a range of pleiotropic effects including vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory effects in both males and females. Relaxin produces these effects by binding to a cognate receptor RXFP1 and activating a variety of signalling pathways including cAMP, cGMP and MAPKs as well as by altering gene expression of TGF-β, MMPs, angiogenic growth factors and endothelin receptors. The peptide has been shown to be effective in halting or reversing many of the adverse effects including fibrosis in animal models of cardiovascular disease including ischaemia/reperfusion injury, myocardial infarction, hypertensive heart disease and cardiomyopathy. Relaxin given to humans is safe and produces favourable haemodynamic changes. Serelaxin, the recombinant form of relaxin, is now in extended phase III clinical trials for the treatment of acute heart failure. Previous clinical studies indicated that a 48 h infusion of relaxin improved 180 day mortality, yet the mechanism underlying this effect is not clear. This article provides an overview of the cellular mechanism of effects of relaxin and summarizes its beneficial actions in animal models and in the clinic. We also hypothesize potential mechanisms for the clinical efficacy of relaxin, identify current knowledge gaps and suggest new ways in which relaxin could be useful therapeutically.

Linked articles: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.

Figure 1

The tissue distribution of RXFP1 receptors and the physiology of relaxin in humans. Relaxin has vasodilatory, anti‐fibrotic and remodelling effects in various reproductive and non‐reproductive organs.

Figure 2

Mechanisms involved in short‐term (minutes) relaxin‐mediated signal transduction in human primary vascular cells.

Figure 3

Effects of longer‐term (hours to days) relaxin administration on expression of genes likely to influence signal transduction in human primary vascular cells.

Figure 4

Relaxin only activates endothelial cells that express cell surface RXFP1 receptors to promote cellular crosstalk between endothelial cells and smooth muscle cells involving NO and, in some endothelial cells, prostanoids.

Figure 5

Therapeutic potential of serelaxin in heart disease and HF. Relaxin therapy mediates fibrosis reversal in rodent models of cardiac fibrosis. There is also strong experimental evidence and clinical evidence for the cardiac protective property of relaxin against factors that function as triggers for cardiac decompensation or acute worsening of HF. These actions would be expected to ameliorate cardiac fibrosis.