Background: Human relaxin‐2 is a peptide hormone capable of pleiotropic effects in several organ systems. Its recombinant formulation (serelaxin) has been demonstrated to reduce infarct size and prevent excessive scar formation in animal models of cardiac ischemia‐reperfusion injury. B7‐33, a synthetically designed peptide analogous to B‐chain of relaxin‐2, invokes signaling at relaxin family peptide receptor 1 (cognate receptor for relaxin‐2) by preferentially phosphorylating the mitogen‐activated protein kinase extracellular signal‐regulated kinase 1/2. We sought to investigate the effects of B7‐33 treatment post ischemia‐reperfusion injury in mice. Methods and Results: Adult male CD 1 mice were subjected to ischemia‐reperfusion via ligation of left anterior descending artery for 30 minutes, followed by 24 hours or 7 days of reperfusion. Echocardiography was performed to assess cardiac function, and cardiac tissue was stained to determine infarct size at 24 hours. B7‐33 significantly reduced infarct size (21.99% versus 45.32%; P =0.02) and preserved fractional shortening (29% versus 23%; P =0.02) compared with vehicle. The difference in fractional shortening further increased at 7 days post myocardial infarction (29% versus 20% for B7‐33 and vehicle groups, respectively). In vitro , primary cardiomyocytes were isolated from adult hearts and subjected to simulated ischemia‐reperfusion injury (simulated ischemia reoxygenation). B7‐33 (50 and 100 nmol/L) improved cell survival and reduced the expression of GRP 78 (glucose regulated protein), an endoplasmic reticulum stress marker. Subsequently, B7‐33 (100 nmol/L) reduced tunicamycin (2.5 μg/mL) induced upregulation of GRP 78 in an extracellular signal‐regulated kinase 1/2–dependent manner. Conclusions: B7‐33 confers acute cardioprotection and limits myocardial infarction–related adverse remodeling in mice by attenuating cardiomyocyte death and endoplasmic reticulum stress as well as preserving cardiac function.

The hormone, relaxin (RLX), exerts various organ-protective effects independently of etiology. However, its complex two-chain and three disulphide bonded structure is a limitation to its preparation and affordability. Hence, a single chain-derivative of RLX, B7-33, was developed and shown to retain the anti-fibrotic effects of RLX in vitro and in vivo. Here, we determined whether B7-33 could retain the other cardioprotective effects of RLX, and also compared its therapeutic efficacy to the ACE inhibitor, perindopril. Adult male 129sv mice were subjected to isoprenaline (ISO; 25 mg/kg/day, s.c)-induced cardiomyopathy, then s.c-treated with either RLX (0.5 mg/kg/day), B7-33 (0.25 mg/kg/day; equivalent dose corrected for MW) or perindopril (1 mg/kg/day) from days 7-14 post-injury. Control mice received saline instead of ISO. Changes in animal body weight (BW) and systolic blood pressure (SBP) were measured weekly, whilst cardiomyocyte hypertrophy and measures of vascular dysfunction and rarefaction, left ventricular (LV) inflammation and fibrosis were assessed at day 14 post-injury. ISO-injured mice had significantly increased LV inflammation, cardiomyocyte hypertrophy, fibrosis, vascular rarefaction and aortic contractility in the absence of any changes in BW or SBP at day 14 post-injury. Both B7-33 and RLX equivalently reduced LV fibrosis and normalised the ISO-induced LV inflammation and cardiomyocyte hypertrophy, whilst restoring blood vessel density and aortic contractility. Comparatively, perindopril lowered SBP and the ISO-induced LV inflammation and vascular rarefaction, but not fibrosis or hypertrophy. As B7-33 retained the cardioprotective effects of RLX and provided rapid-occurring anti-fibrotic effects compared to perindopril, it could be considered as a cost-effective cardioprotective therapy.