Drugs of the future: the hormone relaxin

Abstract

The peptide hormone relaxin is emerging as a multi-functional factor in a broad range of target tissues including several non-reproductive organs, in addition to its historical role as a hormone of pregnancy. This review discusses the evidence that collectively demonstrates the many diverse and vital roles of relaxin: the homeostatic role of endogenous relaxin in mammalian pregnancy and ageing; its gender-related effects; the therapeutic effects of relaxin in the treatment of fibrosis, inflammation, cardioprotection, vasodilation and wound healing (angiogenesis) amongst other pathophysiological conditions, and its potential mechanism of action. Furthermore, translational issues using experimental models (to humans) and its use in various clinical trials, are described, each with important lessons for the design of future trials involving relaxin. The diverse physiological and pathological roles for relaxin have led to the search for its significance in humans and highlight its potential as a drug of the future.

Serelaxin Is a More Efficacious Antifibrotic Than Enalapril in an Experimental Model of Heart Disease

“…In recent studies, we and others have consistently shown that serelaxin is a potent antifibrotic in a wide variety of experimental models and scenarios. [7][8][9][10][11]13,14,[16][17][18][19] Although these studies are important proof of principle, preclinical validation requires a number of additional steps including head-to-head comparison with standard care and validation of therapeutic rather than preventative strategies. These issues are specifically addressed in this study.…”

“…[7][8][9][10] Furthermore, it can ameliorate fibrosis in multiple organs undergoing simultaneous aberrant matrix/collagen accumulation. 11 The collagen-inhibitory actions of relaxin are mediated by its ability to promote nitric oxide-mediated inhibition of Smad2 phosphorylation (pSmad2; an intracellular protein that promotes transforming growth factor [TGF]-β1 signal transduction) 12 and hence the profibrotic actions of TGF-β1.…”

“…15 The antifibrotic efficacy of serelaxin, which is bioactive in mice, 13,14,[16][17][18][19] has also been demonstrated experimentally 13,14,[16][17][18][19] and in patients with early symptoms of scleroderma. [7][8][9] Despite the therapeutic potential of serelaxin as an antifibrotic agent, there has been no direct comparison between serelaxin and current standard of care (eg, ACEi). Hence, this study sought to compare the antifibrotic effects of serelaxin to that of enalapril in a murine model of cardiac fibrosis.…”

Protection from Cigarette Smoke-Induced Lung Dysfunction and Damage by H2 Relaxin (Serelaxin)

“…In this context, serelaxin (RLX), the recombinant molecule corresponding to the human hormone relaxin-2 (Hossain and Wade, 2014), emerges as a feasible candidate. RLX, best known for its effects on reproduction (Sherwood, 2004), also exhibits anti-inflammatory and antifibrotic properties (Masini et al, 2004;Samuel et al, 2007;Bonacchi et al, 2009). In a setting of allergic airway disease, RLX has been shown to inhibit infiltration of proinflammatory cells into the lung and adverse airway remodeling (Bani et al, 1997;Royce et al, 2009Royce et al, , 2014, promote dilation of alveolar blood capillaries, and reduce the thickness of the air-blood barrier (Bani et al, 1997).…”

Expression of LDL-A module of relaxin receptor in prostate cancer cells inhibits tumorigenesis

“…Gene targeting experiments in mice resulted in viable Rln1 and Rxfp1-deficient animals (5-7). Detailed analysis of their phenotype revealed an involvement of this peptide in extracellular matrix remodeling; a fibrosis development was described in various Rln1-or Rxfp1-deficient organs (8). The role of relaxin in regulation of angiogenesis and vasodilation was linked to the induction of vascular endothelial growth factor, up-regulation of nitric oxide synthase, matrix metalloproteases and other factors (9).…”