Human Relaxin-2

What it is

Human Relaxin-2 (serelaxin) is a recombinant form of the endogenous human relaxin-2 peptide hormone, a member of the insulin superfamily originally characterized for its role in reproductive physiology (cervical remodeling, placentation) and now studied for cardiovascular, renal, and hepatic therapeutic applications. It acts through the relaxin family peptide receptor-1 (RXFP1), a Gs- and Gi-coupled GPCR expressed on vascular smooth muscle, endothelial cells, cardiac fibroblasts, renal mesangial cells, hepatic stellate cells, and other tissues (PMID 19073841, PMID 27418970). The primary vascular mechanism is nitric oxide (NO)-dependent vasodilation: RXFP1 activation on endothelial cells increases neuronal/endothelial nitric oxide synthase (nNOS/eNOS) activity, elevating NO and cGMP and producing smooth muscle relaxation and arterial vasodilation. This hemodynamic effect reduces systemic vascular resistance and improves cardiac output — the rationale for use in acute heart failure. Secondary vasodilatory mechanisms include upregulation of endothelin-B receptors and vascular endothelial growth factor (VEGF). The antifibrotic mechanism in kidney, liver, and heart involves suppression of TGF-β1-mediated myofibroblast transformation via RXFP1→nNOS→NO→cGMP-dependent inhibition of Smad2 phosphorylation. In hepatic stellate cells (the fibrosis-mediating cell type), relaxin inhibits collagen synthesis, downregulates TGF-β profibrogenic signaling, and promotes extracellular matrix remodeling via matrix metalloproteinases. In the RELAX-AHF Phase 2 trial (n=234), serelaxin at 30 µg/kg/day IV infusion over 48 hours significantly improved dyspnea relief and reduced in-hospital worsening heart failure vs. placebo, with a post-hoc 180-day mortality benefit. However, the pivotal RELAX-AHF-2 Phase 3 trial (n=6,545; 48h serelaxin 30 µg/kg/day) failed both primary endpoints: cardiovascular death HR 0.98 (p=0.77) and worsening HF HR 0.89 (p=0.19). A biomarker substudy (n=1,020) confirmed serelaxin reduced cardiac troponin T rise (+0.2% vs. +40.3% placebo), creatinine increase (-0.8% vs. +5.8% placebo), and NT-proBNP (-39.8% vs. -27.6% placebo) — suggesting biological organ-protective activity that did not translate to clinical endpoint benefit in RELAX-AHF-2.

Class: Endogenous peptide hormone / RXFP1 receptor agonist / vasodilatory and antifibrotic hormone

What it's studied for

• Acute heart failure — dyspnea relief and worsening heart failure prevention Phase II/III RCT
  • RELAX-AHF-2 Phase 3 RCT (n=6,545 hospitalized AHF patients). 48-hour serelaxin infusion 30 µg/kg/day vs. placebo. Primary endpoints: cardiovascular death at 180 days (8.7% vs 8.9%, HR 0.98, p=0.77); worsening HF at day 5 (6.9% vs 7.7%, HR 0.89, p=0.19). Neither endpoint met. No differences in all-cause mortality, rehos PMID 31433919 Metra M et al. N Engl J Med. 2019.
  • RELAX-AHF-2 design paper: prior Phase 3 data showed serelaxin reduced worsening heart failure by 47% through day 5 and 180-day mortality by 37% (referenced from earlier RELAX-AHF-1 Phase 2 data, n=234). RELAX-AHF-2 enrolled ~6,800 patients at 30 µg/kg/day IV × 48 hours to confirm these effects. Phase 2 (RELAX-AHF-1) po PMID 28452195 Teerlink JR et al. Eur J Heart Fail. 2017.
• End-organ protection — cardiac, renal, and hepatic injury reduction during AHF Phase II/III RCT
  • RELAX-AHF-2 biomarker substudy (n=1,020). Serelaxin vs. placebo through day 14: troponin T change +0.2% vs. +40.3% (cardiac injury); creatinine change -0.8% vs. +5.8% (renal protection); NT-proBNP change -39.8% vs. -27.6% at day 2. Significant reductions in all three markers favoring serelaxin. NT-proBNP and troponin c PMID 39663924 Voors AA et al. Eur J Heart Fail. 2025.
  • Post-hoc RELAX-AHF-1 analysis (n=1,116): serelaxin transiently reduced MELD-XI (hepatorenal function) score at days 2 and 5. Abnormal MELD-XI in 82% of patients on admission predicted 180-day cardiovascular death (HR 3.10) and all-cause death (HR 2.47). Serelaxin's transient MELD-XI reduction suggests a short-lived hep PMID 31568696 Biegus J et al. ESC Heart Fail. 2019.
• Renal fibrosis and myofibroblast inhibition Animal studies only
  • In vitro: human relaxin-2 inhibited α-SMA expression and collagen production in rat renal myofibroblasts exclusively through RXFP1; mechanism requires nNOS-NO-cGMP-Smad2 signaling pathway. In vivo: L-NAME (NO inhibitor) blocked collagen-reducing effects, confirming NO dependence. Establishes RXFP1→nNOS→NO→Smad2 as the PMID 19073841 Mookerjee I et al. FASEB J. 2009.
• Hepatic fibrosis — antifibrotic and anti-stellate cell activation Animal studies only
  • Review: hepatic stellate cells express high-level RXFP1/RXFP2; ML290 (RXFP1 agonist) and serelaxin showed antifibrotic effects in vitro and in vivo. Serelaxin reduced portal hypertension and hepatic fibrosis in experimental models through NO-mediated vasodilation; inhibited collagen synthesis and promoted ECM remodelin PMID 34102254 Ezhilarasan D et al. Biochimie. 2021.
• Cardiovascular hemodynamics — vasodilation and cardiac remodeling Mixed
  • Review: serelaxin improves hemodynamics at vascular, cardiac, and renal levels. Mechanisms include RXFP1-mediated vasodilation (arterial and venous), anti-inflammatory effects, oxidative stress reduction, anti-apoptosis, antifibrosis, and angiogenesis stimulation. Multiple organ protection proposed via pleiotropic sign PMID 27418970 Díez J et al. Eur Heart J Cardiovasc Pharmacother. 2016.
  • Review: relaxin mediates hemodynamic adaptations in pregnancy (vasodilation, increased cardiac output, reduced renal vascular resistance). Serelaxin's Phase 2 AHF results promising; RELAX-AHF-2 outcomes 'rather disappointing.' Reviews cardioprotective mechanisms and explores future directions for exploiting relaxin's b PMID 31642776 Martins RC et al. Curr Mol Med. 2020.

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.

Safety signals

• RELAX-AHF-2 Phase 3 RCT (n=6,545): adverse event incidence comparable between serelaxin 30 µg/kg/day × 48h and placebo. No excess serious adverse events; hemodynamic and renal adverse events not significantly increased vs. placebo. PMID 31433919
• Worsening renal function occurred in 28.2% of RELAX-AHF-2 patients; serelaxin reduced this risk modestly across ejection fraction subgroups but could not prevent it entirely. PMID 32964537
• Serelaxin significantly reduced biomarkers of cardiac (troponin T), renal (creatinine), and hepatic injury compared to placebo through day 14 in a substudy (n=1,020), suggesting organ-protective activity without identified safety signals. PMID 39663924

Contraindications

• Severe renal impairment — RELAX-AHF-2 enrolled patients with mild-to-moderate renal insufficiency; patients with severe renal failure were excluded from the trials. Safety in severe renal impairment is not established. PMID 31433919
• No formal contraindications beyond standard clinical care exclusions established in reviewed literature. Serelaxin is a hospital-administered IV biologic; community self-administration is outside any established evidence base. PMID 27418970