title: Relaxin remodels fibrotic healing following myocardial infarction.
abstract: In the setting of myocardial infarction (MI), implanted stem cell viability is low and scar formation limits stem cell homing, viability, and integration. Thus, interventions that favorably remodel fibrotic healing may benefit stem cell therapies. However, it remains unclear whether it is feasible and safe to remodel fibrotic healing post-MI without compromising ventricular remodeling and dysfunction. This study, therefore, determined the anti-fibrotic and other effects of the hormone, relaxin in a mouse model of MI. Adult male mice underwent left coronary artery ligation-induced MI and were immediately treated with recombinant human relaxin (MI+RLX) or vehicle (MI+VEH) over 7 or 30 days, representing time points of early and mature fibrotic healing. Cardiac function was assessed by echocardiography and catheterization, while comprehensive immunohistochemistry, morphometry, and western blotting were performed to explore the relaxin-induced mechanisms of action post-MI. RLX significantly inhibited the MI-induced progression of cardiac fibrosis over 7 and 30 days, which was associated with a reduction in TGF-β1 expression, myofibroblast differentiation, and cardiomyocyte apoptosis in addition to a promotion of matrix metalloproteinase-13 levels and de novo blood vessel growth (all P<0.05 vs respective measurements from MI+VEH mice). Despite the evident fibrotic healing post-MI, relaxin did not adversely affect the incidence of ventricular free-wall rupture or the extent of LV remodeling and dysfunction. These combined findings demonstrate that RLX favorably remodels the process of fibrotic healing post-infarction by lowering the density of mature scar tissue in the infarcted myocardium, border zone, and non-infarcted myocardium, and may, therefore, facilitate cell-based therapies in the setting of ischemic heart disease.
authors.affiliation: Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia. chrishan.samuel@florey.edu.au
authors.forename: Chrishan S
authors.initials: CS
authors.lastname: Samuel
authors.forename: Sofia
authors.initials: S
authors.lastname: Cendrawan
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.forename: Ziqiu
authors.initials: Z
authors.lastname: Ming
authors.forename: Chongxin
authors.initials: C
authors.lastname: Zhao
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Qi
authors.initials: Q
authors.lastname: Xu
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Tregear
authors.forename: Ross A D
authors.initials: RA
authors.lastname: Bathgate
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005355:Fibrosis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D009929:Organ Size; D012065:Relaxin / Q000627:therapeutic use*; D016896:Treatment Outcome; D020257:Ventricular Remodeling
chemical_list: D012065:Relaxin