Relaxin Family Peptides in Cardiovascular and Fibrotic Disorders

The relaxin family peptides comprise a group of structurally related hormones, including relaxin-1, relaxin-2 and relaxin-3, as well as insulin-like peptides (INSLs). Relaxin-2 is the principal circulatory form and exerts vasodilatory, anti-fibrotic and anti-inflammatory effects through activation of G-protein-coupled receptors (notably RXFP1). In the cardiovascular system, relaxin signalling promotes endothelial nitric oxide production, modulates extracellular matrix remodelling via matrix metalloproteinases and inhibits TGF-β-driven fibroblast-to-myofibroblast transition. In fibrotic disorders of heart, kidney and other organs, relaxin peptides counteract collagen deposition, suppress pro-inflammatory cytokines and enhance tissue repair. Advances in receptor pharmacology and delivery technologies have underpinned novel therapeutic strategies for acute heart failure, chronic kidney disease and hypertensive organ damage, highlighting the global potential of relaxin-based interventions.

Research from Nature Portfolio

Recent studies have characterised ML290, a small-molecule biased allosteric agonist of RXFP1, which selectively couples the receptor to Gαs and GαoB subunits. In human vascular endothelial and smooth muscle cells ML290 potently stimulates cAMP and cGMP formation and p38 MAPK phosphorylation, while in cardiac fibroblasts it inhibits TGF-β-induced Smad2/3 activation and up-regulates MMP-2 expression. This bias in downstream signalling confers sustained anti-fibrotic and vasodilatory effects and establishes ML290 as a lead compound for oral relaxin-mimetic therapeutics.

Relaxin Family Peptides in Cardiovascular and Fibrotic Disorders publication trend

The graph below shows the total number of articles in relaxin family peptides in cardiovascular and fibrotic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Relaxin Family Peptides: A group of peptide hormones structurally related to insulin, including relaxin-1, relaxin-2, relaxin-3 and insulin-like peptides, involved in reproductive, cardiovascular and fibrotic processes.

RXFP1: Relaxin family peptide receptor 1, a G-protein-coupled receptor mediating most cardiovascular and anti-fibrotic actions of relaxin-2.

Fibroblast-Myofibroblast Transition: The process by which quiescent fibroblasts acquire contractile, collagen-secreting myofibroblast phenotype under profibrotic stimuli, notably TGF-β.

Mesenchymal Stromal Cells: Multipotent progenitor cells capable of homing to injured tissue, here engineered to express and deliver relaxin-2 for antifibrotic therapy.

AMPK-SIRT1 Pathway: A cellular energy-sensing and survival signalling cascade in which AMP-activated protein kinase activates the sirtuin 1 deacetylase, promoting mitochondrial efficiency and stress resistance.

References

1. Cellular delivery of relaxin-2 mRNA as a potential treatment for kidney fibrosis. Materials Today Bio (2023).
2. The renoprotective efficacy and safety of genetically-engineered human bone marrow-derived mesenchymal stromal cells expressing anti-fibrotic cargo. Stem Cell Research & Therapy (2024).
3. Serelaxin Protects H9c2 Cardiac Myoblasts against Hypoxia and Reoxygenation-Induced Damage through Activation of AMP Kinase/Sirtuin1: Further Insight into the Molecular Mechanisms of the Cardioprotection of This Hormone. Antioxidants (2024).
4. Relaxin Prevents Cardiac Fibroblast-Myofibroblast Transition via Notch-1-Mediated Inhibition of TGF-β/Smad3 Signaling. PLOS ONE (2013).
5. Relaxin Signals through a RXFP1-pERK-nNOS-NO-cGMP-Dependent Pathway to Up-Regulate Matrix Metalloproteinases: The Additional Involvement of iNOS. PLOS ONE (2012).
6. ML290 is a biased allosteric agonist at the relaxin receptor RXFP1. Scientific Reports (2017).