Relaxin-2 (Serelaxin)

Mechanism

Relaxin-2 signals primarily through the relaxin family peptide receptor 1 (RXFP1), a G protein-coupled receptor with a large extracellular leucine-rich repeat domain. Binding of relaxin-2 to RXFP1 activates multiple downstream signalling cascades:

1. Vasodilation: Relaxin-2 increases endothelial nitric oxide synthase (eNOS) activity, leading to nitric oxide production and vasorelaxation. It also modulates the endothelin system (upregulating ET-B receptors which promote vasodilation) and increases VEGF expression.

2. Antifibrosis: Relaxin-2 inhibits fibroblast differentiation into myofibroblasts and reduces collagen synthesis. It upregulates matrix metalloproteinases (MMPs, particularly MMP-2 and MMP-9) while downregulating tissue inhibitors of metalloproteinases (TIMPs), promoting extracellular matrix degradation and reducing fibrotic scarring. This involves suppression of TGF-beta signalling, a master regulator of fibrosis.

3. Anti-inflammation: Relaxin-2 reduces pro-inflammatory cytokine production (TNF-alpha, IL-6, IL-1beta) and macrophage infiltration in inflamed tissues.

4. Angiogenesis: Through VEGF upregulation and nitric oxide pathways, relaxin-2 promotes new blood vessel formation, which underlies its wound-healing and cardiovascular research interest.

5. Renal effects: In pregnancy, relaxin-2 increases renal plasma flow and glomerular filtration rate through renal vasodilation, an effect being explored for therapeutic applications in kidney disease.

Evidence base

Evidence Grade: Moderate

Strengths: Large Phase 3 clinical trial programme (RELAX-AHF); strong mechanistic basis for antifibrotic and vasodilatory effects; extensive preclinical data across multiple organ systems.

Limitations: Pivotal confirmatory trial (RELAX-AHF-2, n=6545) failed to meet primary endpoints; no regulatory approval worldwide; most antifibrotic evidence is preclinical (animal models).

Key studies:

• Metra M et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program. J Am Coll Cardiol. 2013;61(2):196–206.
• Teerlink JR et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF-2). Lancet. 2018;391(10120):430–440.
• Du XJ et al. Cardiovascular effects of relaxin: from basic science to clinical therapy. Nat Rev Cardiol. 2010;7(1):48–58.
• Samuel CS et al. Relaxin as a modulator of fibrosis: promising therapeutic target? Heart Fail Rev. 2021;26(1):137–154.

Protocols

Serelaxin was administered as a 30 microg/kg per day intravenous infusion for 48 hours in the RELAX-AHF clinical trials. In preclinical research, relaxin-2 is typically administered subcutaneously at doses of 0.1 to 10 microg/kg, with treatment duration ranging from days (acute models) to weeks (chronic fibrosis models). These protocols are described for research documentation only; relaxin-2 is not licensed for human use in the UK.

UK legal status

Relaxin-2/serelaxin is not a licensed medicine in the UK, not MHRA-registered, and not a controlled substance. Following the negative RELAX-AHF-2 trial, Novartis withdrew regulatory submissions in the US and EU. Serelaxin is not approved by the FDA or EMA for any indication. It may be sold for research purposes under standard research-peptide regulations. The clinical evidence is mixed, with early heart failure promise not confirmed in the pivotal trial.

Vendor notes

Recombinant relaxin-2 has limited availability from standard research peptide suppliers, as it is a more complex two-chain peptide requiring proper folding and disulphide bond formation. Researchers should verify that sourced material is biologically active (properly folded) and not just a linear peptide, as biological activity depends on correct three-dimensional structure. COA verification is essential.