Relaxin

Overview

Relaxin is a peptide hormone belonging to the insulin superfamily, first identified by Frederick Hisaw in 1926 through its ability to relax the pubic symphysis in guinea pigs. In humans, relaxin is produced primarily by the corpus luteum during pregnancy, though it is also expressed in smaller quantities by the prostate, atria, decidua, and other tissues in both sexes.

The relaxin family in humans comprises seven peptides (relaxin-1, -2, -3, and insulin-like peptides 3, 4, 5, 6), but relaxin-2 (H2 relaxin, encoded by the RLN2 gene) is the primary circulating form and the focus of most clinical research. It plays essential roles in the physiological adaptations of pregnancy, particularly in connective tissue remodeling, vascular dilation, and renal hemodynamic changes.

Beyond pregnancy physiology, relaxin has attracted substantial research interest for its cardiovascular, anti-fibrotic, and vasodilatory properties. The recombinant form, serelaxin (RLX030), was evaluated in large-scale clinical trials for acute heart failure, representing one of the most significant peptide drug development programs in cardiovascular medicine of the 2010s.

Structure and Sequence

Relaxin-2 is structurally homologous to insulin, consisting of two peptide chains linked by disulfide bonds:

• A chain: 24 amino acids
• B chain: 29 amino acids
• Disulfide bonds: Two inter-chain (A-B) bonds and one intra-chain (A chain) bond, identical in topology to insulin
• Molecular weight: approximately 5,963 g/mol
• Key structural features: Unlike insulin, relaxin has a distinct receptor-binding domain located at the B chain surface. The critical binding residues include Arg13, Arg17, and Ile/Val20 on the B chain, forming a receptor-binding cassette that is conserved across species.
• Synthesis: Produced as a preprorelaxin precursor, processed through removal of signal peptide and C-peptide (analogous to proinsulin processing)

Mechanism of Action

Receptor Signaling

Relaxin-2 signals primarily through the relaxin family peptide receptor 1 (RXFP1), a leucine-rich repeat-containing G-protein coupled receptor:

RXFP1 activation:

• Binding to the large ectodomain of RXFP1 triggers conformational changes in the transmembrane domain
• Activates both Gs (stimulating adenylyl cyclase and cAMP production) and Gi3 (through a delayed, PI3K-dependent mechanism)
• Downstream signaling includes activation of PKA, Akt/PKB, ERK1/2, and nitric oxide synthase (NOS) pathways
• The cGMP-nitric oxide pathway is particularly important for vascular effects
• Additionally activates matrix metalloproteinase (MMP) expression, contributing to extracellular matrix remodeling

Tissue-specific effects:

Reproductive tract:

• Remodeling of the cervix and vaginal wall (increased collagen turnover, water content, glycosaminoglycan deposition)
• Relaxation of the pubic symphysis (more prominent in rodents than humans)
• Decidualization of endometrial stroma
• Growth and development of mammary gland parenchyma

Cardiovascular system:

• Vasodilation through endothelium-dependent NO release
• Increased arterial compliance and reduced systemic vascular resistance
• Positive chronotropic effects (mild heart rate increase)
• Anti-inflammatory effects on vascular endothelium
• Stimulation of angiogenesis through VEGF upregulation

Renal system:

• Increased renal plasma flow and glomerular filtration rate
• Reduced myogenic reactivity of renal afferent arterioles
• These effects contribute to the 40-50% increase in GFR observed during normal pregnancy

Fibrosis modulation:

• Inhibition of fibroblast-to-myofibroblast transition
• Reduced collagen synthesis and deposition via TGF-beta signaling interference
• Increased MMP activity promoting extracellular matrix turnover

Research Summary

Pharmacokinetics

Pharmacokinetic data below refer primarily to serelaxin (recombinant human relaxin-2) as studied in clinical trials:

• Route: intravenous infusion (serelaxin); endogenous relaxin is secreted into the circulation
• Half-life: approximately 2-3 hours (serelaxin IV infusion)
• Endogenous levels in pregnancy: peak at approximately 1-2 ng/mL during the first trimester, declining slightly through the second and third trimesters
• Endogenous levels (non-pregnant): largely undetectable in women; detectable at low levels in male serum
• Metabolism: primarily by renal and hepatic peptidases
• Clearance: rapid clearance necessitated continuous IV infusion in clinical trials (48-hour infusion protocol in RELAX-AHF)
• Distribution: limited volume of distribution consistent with vascular and extracellular fluid compartments
• Protein binding: minimal

Common Discussion Topics

Failure of RELAX-AHF-2

The RELAX-AHF trial generated considerable excitement when serelaxin showed a significant reduction in 180-day cardiovascular mortality as a secondary endpoint. However, the larger confirmatory RELAX-AHF-2 trial (6,600 patients) failed to replicate this benefit, and the drug did not achieve regulatory approval for acute heart failure. This outcome is frequently discussed as an example of the challenges in confirming secondary endpoint signals in cardiovascular medicine, and the difficulty of translating hemodynamic improvements into mortality benefits.

Anti-Fibrotic Potential

Relaxin's ability to reverse established fibrosis in preclinical models of cardiac, hepatic, renal, and pulmonary fibrosis has sustained research interest despite the heart failure setback. The anti-fibrotic mechanism — involving inhibition of TGF-beta signaling, reduction of Smad2 phosphorylation, and upregulation of MMPs — is well characterized in animal models. The challenge remains translating these findings into clinical efficacy, particularly given relaxin's short half-life and the need for prolonged treatment to reverse fibrosis.

Relaxin in Pregnancy Complications

The observation that women with low early-pregnancy relaxin levels have increased risk of preeclampsia and other hypertensive disorders has stimulated interest in relaxin as both a biomarker and potential therapeutic in pregnancy complications. The physiological role of relaxin in mediating the hemodynamic adaptations of pregnancy (increased cardiac output, decreased vascular resistance, increased renal blood flow) provides mechanistic rationale for this association.

Long-Acting Relaxin Analogs

The short half-life of native relaxin-2 has driven efforts to develop longer-acting formulations. Approaches under investigation include Fc-fusion proteins, PEGylated analogs, and engineered single-chain relaxin variants. A long-acting analog suitable for subcutaneous injection would open possibilities for chronic disease applications (e.g., fibrosis) that are impractical with continuous IV infusion.

Dosing Protocols

The following information is compiled from published clinical trial data for educational purposes only. Always consult a qualified healthcare professional.

Recombinant human relaxin-2 (serelaxin, developed by Novartis) was investigated for acute heart failure but failed to meet primary endpoints in the Phase 3 RELAX-AHF-2 trial and is not approved for clinical use.

As an endogenous hormone, relaxin is primarily studied as a biomarker of pregnancy physiology and connective tissue remodeling, or through its investigational therapeutic applications in heart failure, fibrosis, and preeclampsia.

Related Compounds

• Atrial Natriuretic Peptide — A cardiac peptide hormone with complementary vasodilatory and natriuretic effects, relevant to cardiovascular peptide biology
• Secretin — Another peptide hormone with systemic physiological roles, sharing the context of peptide hormones with clinical applications
• Glucagon — A pancreatic peptide hormone with cardiovascular effects (positive inotropy) relevant to comparative peptide pharmacology