Relaxin-2

Relaxin-2 signals primarily through Relaxin Family Peptide Receptor 1 (RXFP1), a leucine-rich repeat-containing GPCR. RXFP1 activation increases cAMP via Gs coupling and activates NO synthase through PI3K/Akt signaling. The resulting NO and cAMP production mediates vasodilation of renal, hepatic, and systemic vasculature. RXFP1 is also expressed in cardiac fibroblasts, where relaxin suppresses collagen synthesis and activates matrix metalloproteinases that remodel fibrotic tissue.

Relaxin-2 inhibits TGF-beta-driven collagen synthesis in fibroblasts through SMAD2/3 pathway suppression and upregulation of matrix metalloproteinases (MMP-1, MMP-2, MMP-9). These converging effects both prevent new fibrosis and actively degrade established fibrotic matrix. This dual action on fibrosis represents one of the few validated anti-fibrotic mechanisms with clinical efficacy data.

The RELAX-AHF-1 Phase III trial of serelaxin in 1161 acute heart failure patients showed significant reduction in dyspnea scores and a 37% reduction in 180-day cardiovascular mortality. RELAX-AHF-2 enrolled 6600 patients but did not confirm the mortality benefit. Organ-protective biomarker improvements (troponin, creatinine) were consistently observed.

Serelaxin treatment consistently reduced markers of renal and hepatic injury (creatinine, transaminases) in heart failure trials, suggesting broad organ protection beyond cardiac effects. These organ-protective properties are under investigation for acute kidney injury and liver fibrosis.

Animal models of cardiac, pulmonary, renal, and hepatic fibrosis consistently show relaxin treatment reduces fibrotic burden and preserves organ function. Relaxin treatment reversed established cardiac fibrosis in several models, a finding with broad implications for chronic fibrotic disease therapy.