Reperfusion therapy with recombinant human relaxin-2 (Serelaxin) attenuates myocardial infarct size and NLRP3 inflammasome following ischemia/reperfusion injury via eNOS-dependent mechanism

Cardiovasc Res. 2017 May 1;113(6):609-619. doi: 10.1093/cvr/cvw246.


Aims: The preconditioning-like infarct-sparing and anti-inflammatory effects of the peptide hormone relaxin following ischemic injury have been studied in the heart. Whether reperfusion therapy with recombinant human relaxin-2, serelaxin, reduces myocardial infarct size and attenuates the subsequent NLRP3 inflammasome activation leading to further loss of functional myocardium following ischemia/reperfusion (I/R) injury is unknown.

Methods and results: After baseline echocardiography, adult male wild-type C57BL or eNOS knockout mice underwent myocardial infarction (MI) by coronary artery ligation for 30 min followed by 24 h reperfusion. Mice were treated with either serelaxin (10 µg/kg; sc) or saline 1 h prior to ischemia or 5 min before reperfusion. In both pre-treatment and reperfusion therapy arms, serelaxin improved survival at 24 h post MI in wild-type mice (79% and 82%) as compared with controls (46% and 50%, P = 0.01), whereas there was no difference in survival between serelaxin- and saline-treated eNOS knockout mice. Moreover, serelaxin significantly reduced infarct size (64% and 67% reduction, P < 0.05), measured with TTC staining, and preserved LV fractional shortening (FS) and end-systolic diameter (LVESD) in wild-type mice as compared with controls (P < 0.05). Interestingly, caspase-1 activity in the heart tissue, a measure of inflammasome formation, was markedly reduced in serelaxin-treated wild-type mice compared with controls at 24 h post-MI in both treatment modalities (P < 0.05). Genetic deletion of eNOS abolished the infarct-sparing and anti-inflammatory effects of serelaxin as well as functional preservation. Serelaxin plasma levels assessed at 5 min and 1 h after treatment, using ELISA, approximated physiologic relaxin levels during pregnancy in mice and parallels that in humans.

Conclusion: Serelaxin attenuates myocardial I/R injury and the subsequent caspase-1 activation via eNOS-dependent mechanism.

Keywords: Caspase-1; Ischemia-reperfusion injury; LV function; Serelaxin; eNOS.

MeSH terms

  • Animals
  • Cardiovascular Agents / pharmacology*
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Inflammasomes / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control*
  • Myocardial Reperfusion / adverse effects
  • Myocardial Reperfusion / methods*
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / enzymology*
  • Myocardium / pathology
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Nitric Oxide Synthase Type III / deficiency
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism*
  • Nitrites / blood
  • Rats
  • Receptors, G-Protein-Coupled / metabolism
  • Recombinant Proteins / pharmacology
  • Relaxin / pharmacology*
  • Signal Transduction / drug effects
  • Time Factors
  • Ventricular Function, Left / drug effects


  • Cardiovascular Agents
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nitrites
  • Nlrp3 protein, mouse
  • RXFP1 protein, mouse
  • Receptors, G-Protein-Coupled
  • Recombinant Proteins
  • serelaxin protein, human
  • Relaxin
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Caspase 1