Human Relaxin-2, or serelaxin in its recombinant form, is a peptide hormone that acts primarily through the RXFP1 receptor to induce systemic and renal vasodilation via nitric oxide and bradykinin pathways. It is primarily studied for its ability to reduce vascular resistance, improve organ perfusion, and exhibit anti-fibrotic and anti-inflammatory properties in cardiovascular and liver diseases.

Overview

Human relaxin-2 (H2 relaxin) is a 6-kDa peptide hormone belonging to the insulin superfamily, consisting of two chains (A and B) linked by disulfide bonds. Originally identified for its role in reproductive physiology — cervical ripening, mammary gland development, and uterine relaxation during pregnancy — relaxin-2 has emerged as a potent cardiovascular and anti-fibrotic agent with far-reaching therapeutic implications. It signals primarily through the relaxin family peptide receptor 1 (RXFP1), a G-protein coupled receptor expressed in the heart, kidneys, vasculature, liver, lungs, and brain.

The cardiovascular effects of relaxin-2 are multifaceted. It promotes systemic and renal vasodilation through stimulation of nitric oxide (NO) and vascular endothelial growth factor (VEGF) pathways, increases arterial compliance, and reduces systemic vascular resistance. In the RELAX-AHF trial, serelaxin (recombinant human relaxin-2) demonstrated significant improvement in dyspnea and a reduction in 180-day cardiovascular mortality in patients with acute heart failure, though subsequent trials showed mixed results. Its anti-fibrotic properties are particularly notable — relaxin-2 inhibits TGF-β/Smad signaling, reduces collagen deposition, and promotes matrix metalloproteinase (MMP) activity to reverse established fibrosis in cardiac, renal, pulmonary, and hepatic tissues.

Beyond heart failure, relaxin-2 is under investigation for fibrotic conditions including scleroderma, pulmonary fibrosis, and chronic kidney disease. Its vasodilatory and anti-fibrotic mechanisms complement those of peptides like BPC-157 in tissue remodeling and thymosin-beta-4 in wound healing. The relatively short half-life of native relaxin-2 (approximately 10 minutes) has driven development of extended-release formulations and long-acting analogs. Research into RXFP1 small-molecule agonists continues, aiming to capture relaxin-2's therapeutic benefits in an orally bioavailable format for chronic fibrotic and cardiovascular diseases.

Mechanism of Action

RXFP1 Receptor Activation & G-Protein Signaling

Human relaxin-2 is a 6-kDa heterodimeric peptide hormone of the insulin superfamily, consisting of A and B chains linked by disulfide bonds. Its primary receptor is relaxin family peptide receptor 1 (RXFP1), a leucine-rich repeat-containing G-protein coupled receptor (LGR7). Relaxin-2 binds to RXFP1 via two interaction sites: the B-chain engages the leucine-rich repeat ectodomain while the A-chain contacts the transmembrane exoloops. This dual binding activates Gs-coupled adenylyl cyclase, increasing intracellular cAMP and activating protein kinase A (PKA) (PMID: 23619623).

Nitric Oxide & Vasodilatory Pathway

A hallmark of relaxin-2 signaling is activation of the PI3K/Akt/eNOS cascade, leading to sustained nitric oxide (NO) production. NO activates soluble guanylyl cyclase and increases cGMP, producing profound vasodilation. In the renal vasculature, this results in increased renal plasma flow and glomerular filtration rate. Systemically, relaxin-2-induced vasodilation reduces systemic vascular resistance, contributing to the hemodynamic adaptations of pregnancy (PMID: 20550920).

Anti-Fibrotic Mechanisms

Relaxin-2 is a potent anti-fibrotic agent that acts through multiple mechanisms: it inhibits TGF-beta1/Smad2/3 signaling in fibroblasts, reducing collagen I and III synthesis; it upregulates matrix metalloproteinases (MMP-1, MMP-2, MMP-9) while downregulating tissue inhibitors of metalloproteinases (TIMPs), promoting extracellular matrix degradation; and it inhibits myofibroblast differentiation by suppressing alpha-smooth muscle actin (alpha-SMA) expression. These effects are mediated through both cAMP/PKA and NO/cGMP-dependent pathways.

Cardiac & Renal Protective Effects

In the heart, relaxin-2 exerts positive inotropic and chronotropic effects via cAMP-mediated enhancement of L-type calcium channel activity and increased calcium sensitivity. It protects against cardiac fibrosis and ischemia-reperfusion injury through its combined vasodilatory, anti-fibrotic, and anti-inflammatory actions, making recombinant relaxin-2 (serelaxin) an investigational therapeutic for acute heart failure.

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Research

Safety Profile

Safety Profile: Human Relaxin-2 (Serelaxin / RLX-2)

Common Side Effects

• Hypotension (dose-dependent blood pressure reduction is a primary pharmacological effect)
• Headache (commonly reported in clinical trials)
• Nausea and vomiting
• Dizziness related to vasodilation
• Injection site reactions (erythema, pain, swelling) with subcutaneous administration
• Flushing and warmth sensation

Serious Adverse Effects

• Significant hypotension: Can cause symptomatic low blood pressure, particularly in volume-depleted patients or those on antihypertensives; may lead to syncope, falls, or end-organ hypoperfusion
• Renal impairment: Relaxin-2 affects renal hemodynamics; excessive vasodilation may impair renal perfusion in susceptible individuals
• Cardiac events: In the RELAX-AHF-2 trial, serelaxin did not reduce cardiovascular death; monitoring for worsening heart failure symptoms is essential
• Immunogenicity: Anti-drug antibodies may develop with repeated administration of recombinant protein
• Tissue remodeling: Relaxin-2 promotes extracellular matrix remodeling and collagen turnover; long-term effects on connective tissue integrity are unknown

Contraindications

• Systolic blood pressure <100 mmHg or symptomatic hypotension
• Severe renal impairment (eGFR <30 mL/min) without close monitoring
• Known hypersensitivity to serelaxin or any excipient
• Concurrent use of multiple antihypertensives with high hypotension risk
• Conditions requiring intact connective tissue stability (e.g., aortic aneurysm, Ehlers-Danlos syndrome) — theoretical concern
• Pregnancy (outside of obstetric indications under specialist care)

Drug Interactions

• Antihypertensives (ACE inhibitors, ARBs, calcium channel blockers, diuretics): Additive blood pressure reduction; significant hypotension risk
• Nitrates: Profound vasodilation and hypotension
• PDE5 inhibitors (sildenafil, tadalafil): Additive vasodilation; avoid concurrent use
• Diuretics: Additive volume depletion; monitor fluid status and renal function
• NSAIDs: May attenuate relaxin's renal vasodilatory effects
• Other vasodilators: Additive hypotensive effects

Population-Specific Considerations

• Heart failure patients: Studied in acute heart failure (RELAX-AHF trials); showed early symptom improvement but failed to demonstrate mortality benefit in RELAX-AHF-2
• Pregnancy: Relaxin is a natural pregnancy hormone; therapeutic use requires obstetric specialist oversight
• Elderly: Higher sensitivity to hypotension; careful dose titration and blood pressure monitoring required
• Renal impairment: Affects renal hemodynamics; monitor eGFR and serum creatinine closely
• Connective tissue disorders: Theoretical concern regarding tissue remodeling; avoid in patients with connective tissue fragility
• Note: Novartis discontinued development of serelaxin after the RELAX-AHF-2 trial failed its primary endpoint; availability is limited to research settings

Pharmacokinetic Profile