Regenerative Research
Serelaxin: Decoding the Heart of a Hormone-Inspired Peptide
·Educational reference
Imagine a hormone that orchestrates remarkable cardiovascular and renal adaptations during pregnancy, allowing the body to support two lives. Now, imagine harnessing that natural power in a lab-made peptide to tackle some of humanity's most challenging diseases. This is the story of serelaxin, a synthetic form of human relaxin-2, a peptide that has generated considerable excitement in the medical community for its potential to address acute heart failure and fibrotic conditions.
What is Serelaxin?
Serelaxin is a recombinant version of human relaxin-2, a naturally occurring peptide hormone (PMID 26603680). Relaxin-2 is known to mediate many of the adaptive hemodynamic changes seen during pregnancy (PMID 26603680, PMID 31433919). Researchers have observed its vasodilatory effects, which primarily involve nitric oxide, leading to increased renal plasma flow (PMID 27727514). Beyond its vascular actions, serelaxin has also been found to increase the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2 and MMP-9 (PMID 27727514).
Why researchers are excited
The physiological actions of natural relaxin, particularly its hemodynamic effects like decreasing pulmonary and systemic resistance and increasing renal blood flow, suggested that a recombinant version could be beneficial for treating acute heart failure (AHF) (PMID 26603680). The peptide’s vasodilatory, anti-fibrotic, and anti-inflammatory properties have fueled optimism for its therapeutic use (PMID 27727514, PMID 33687895).
Early clinical development showed promise. Phase II studies, for example, indicated reductions in pulmonary arterial pressure, pulmonary capillary wedge pressure, and NT-proBNP in patients (PMID 27727514). These findings, coupled with preclinical evidence of its organ-protective qualities, highlighted serelaxin as a potential candidate for a range of conditions, including chronic heart failure, coronary artery disease, portal hypertension, and acute renal failure (PMID 28009437).
What the studies found
Research on serelaxin has spanned from cellular and animal models to large-scale human clinical trials, revealing a complex picture of its effects.
| Study | Model | Key finding | PMID | |---|---|---|---| | RELAX-AHF (Phase III) | 1161 AHF patients | Significant improvement in symptoms, reduced worsening of heart failure, decreased hospital length of stay, and increased 180-day survival (compared to placebo) | PMID 26603680, PMID 27727514 | | RELAX-AHF-2 (Phase III) | 6545 AHF patients | No significant difference in 180-day cardiovascular death or 5-day worsening heart failure (compared to placebo) | PMID 31433919 | | Uninephrectomized rats | DOCA-salt hypertensive rats | Prevented cardiac and renal dysfunction, fibrosis, inflammation, and decreased lipid accumulation | PMID 28851937 | | Systematic review & meta-analysis | 8 RCTs (8477 participants) | No effect on 30-day, 60-day, or 180-day mortality, or on dyspnea improvement (compared to other heart failure treatments/control) | PMID 29923986 |
In animal studies, serelaxin showed a robust range of benefits. In a model of DOCA-salt hypertensive rats, treatment with serelaxin prevented both cardiac and renal dysfunction. It also prevented cardiac and renal fibrosis, reduced renal inflammation (including markers like TGF-β, NFκB, MCP-1, IL-1, IL-6, ICAM-1, VCAM-1, and CD68 macrophages), and decreased lipid accumulation in the kidney (PMID 28851937). These findings suggest broad protective effects in a preclinical setting.
However, the journey in human trials has been more nuanced. An earlier 1161-patient, placebo-controlled Phase III trial, RELAX-AHF, demonstrated significant improvements in symptoms, reduced worsening of heart failure, decreased hospital length of stay, and increased 180-day survival after hospitalization for acute heart failure (PMID 26603680, PMID 27727514). This trial opened new avenues into understanding its effects (PMID 27727514).
Subsequent, larger Phase III trials, including RELAX-AHF-2, involving 6545 patients, presented a different outcome. In this multicenter, double-blind, placebo-controlled trial, serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days compared to placebo. There were also no significant differences in other outcomes such as overall mortality, rehospitalization for heart failure or renal failure, or length of hospital stay (PMID 31433919). A systematic review and meta-analysis of 8 randomized controlled trials, including 8477 participants, concluded that serelaxin had no effect on 30-day, 60-day, or 180-day mortality, nor did it improve dyspnea in heart failure patients when compared to other treatments or control groups (PMID 29923986).
How it's thought to work
Serelaxin, like its natural counterpart relaxin-2, is believed to exert its effects through several key mechanisms. Its primary actions are vasodilatory, largely mediated by nitric oxide, which contributes to observed increases in renal plasma flow (PMID 27727514). This vasodilation helps decrease pulmonary and systemic resistance (PMID 26603680).
Beyond vascular effects, serelaxin has demonstrated anti-fibrotic and anti-inflammatory properties (PMID 27727514). In particular, *in vitro* and *in vivo* studies suggest relaxin promotes extracellular matrix remodeling by inhibiting multiple fibrogenic pathways. This includes targeting the downstream signaling of transforming growth factor (TGF)-β1, a major pro-fibrotic cytokine, and the recruitment and activation of myofibroblasts, which are key cells in fibrosis generation (PMID 33687895). It also increases the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2 and MMP-9 (PMID 27727514). In animal models, serelaxin was shown to decrease markers of inflammation like TGF-β and NFκB, and reduce lipid accumulation in the kidney by modulating gene expression related to lipid synthesis and transport (PMID 28851937).
The catch: what we still don't know
Despite promising preclinical findings and an initial positive Phase III trial for acute heart failure, subsequent large-scale clinical trials have yielded inconclusive or negative results regarding serelaxin's impact on key endpoints like mortality and worsening heart failure (PMID 31433919, PMID 29923986). While the RELAX-AHF trial showed some benefits, the RELAX-AHF-2 trial, a larger study, did not replicate these findings for primary endpoints (PMID 31433919). This highlights the complex challenge of translating preclinical success into consistent clinical outcomes.
Researchers are still trying to understand why results have varied. The initial positive outcomes in the RELAX-AHF trial and the preclinical animal data (PMID 26603680, PMID 28851937) suggest that serelaxin does have biological activity. However, the exact patient populations, timing of administration, or specific disease mechanisms where it might be most effective are still being investigated (PMID 33687895). The field is actively re-appraising past clinical trials to identify strengths, weaknesses, and future opportunities for serelaxin or its analogues, particularly in fibrotic diseases and pathologic scarring (PMID 33687895).
Keep exploring
The journey of serelaxin underscores the meticulous nature of peptide research, where initial excitement often gives way to rigorous testing and refinement. While its path to a clear therapeutic role is still evolving, the insights gained from studying serelaxin continue to deepen our understanding of cardiovascular and fibrotic diseases. We invite you to browse our A–Z protocols, compare compounds, and share this article to contribute to the ongoing conversation in peptide science.