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 þ RLX) or vehicle (MI þ 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-b1 expression, myofibroblast differentiation, and cardiomyocyte apoptosis in addition to a promotion of matrix metalloproteinase-13 levels and de novo blood vessel growth (all Po0.05 vs respective measurements from MI þ 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.

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

“…Moreover, the vasodilatory attributes of RLN, particularly in the renal circulation, as detailed in this review, as well as other salutary properties, including the potential to improve arterial stiffness (34,42), suggested the therapeutic use of RLN in heart failure (34,191). In further support of this idea are more recent findings that RLN improves cardiac fibrosis (153,166) and mobilizes and increases the activity of bone marrow angiogenic progenitor cells (170). Indeed, a recent phase III study of RLN in acute heart failure appears promising (190).…”

Serelaxin Is a More Efficacious Antifibrotic Than Enalapril in an Experimental Model of Heart Disease

“…13,14 Recent phase III clinical trials have successfully evaluated the vasodilatory properties of serelaxin (a recombinant form of human gene-2 relaxin, which is the major stored and circulating form of relaxin in humans) in acute heart failure. 15 The antifibrotic efficacy of serelaxin, which is bioactive in mice, 13,14,[16][17][18][19] has also been demonstrated experimentally 13,14,[16][17][18][19] and in patients with early symptoms of scleroderma. [7][8][9] Despite the therapeutic potential of serelaxin as an antifibrotic agent, there has been no direct comparison between serelaxin and current standard of care (eg, ACEi).…”

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

“…In the phase 3 RELAX‐AHF (Serelaxin, Recombinant Human Relaxin‐2, for Treatment of Acute Heart Failure) trial of patients with acute heart failure, those who received a 16‐hour infusion of serelaxin showed improvements in biomarker expression patterns reflecting cardiac, renal, and hepatic damage, and these improvements correlated with reductions in all‐cause mortality by day 180 39, 41. In animal models, serelaxin and other formulations of recombinant relaxin‐2 have been shown to be protective in experimental models of cardiac injury 15, 16, 17, 18, 42, 43…”

“…Relaxin‐2 overexpression by systemic adenovirus delivery attenuates cardiac collagen deposition in mice that overexpress the β2‐adrenergic receptor 14. Moreover, the antifibrotic actions of recombinant human relaxin‐2 have been demonstrated in various cardiac disease models, including myocardial infarction,15 diabetic cardiomyopathy,16 and isoproterenol‐induced cardiac injury,17 and in the spontaneously hypertensive rat 18…”