title: Reperfusion therapy with recombinant human relaxin-2 (Serelaxin) attenuates myocardial infarct size and NLRP3 inflammasome following ischemia/reperfusion injury via eNOS-dependent mechanism.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Serelaxin attenuates myocardial I/R injury and the subsequent caspase-1 activation via eNOS-dependent mechanism.
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Valle Raleigh
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Adolfo G
authors.initials: AG
authors.lastname: Mauro
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Teja
authors.initials: T
authors.lastname: Devarakonda
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Marchetti
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Kim
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Filippone
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Anindita
authors.initials: A
authors.lastname: Das
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.affiliation: Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-070, Richmond, VA 23298-0204, USA.
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015425:Myocardial Reperfusion / Q000009:adverse effects / Q000379:methods*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012065:Relaxin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002317:Cardiovascular Agents; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009573:Nitrites; C492716:Nlrp3 protein, mouse; C478103:RXFP1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; C577649:serelaxin protein, human; D012065:Relaxin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020170:Caspase 1
keywords: Caspase-1; Ischemia-reperfusion injury; LV function; Serelaxin; eNOS