1. Academic Validation
  2. The single-chain relaxin mimetic, B7-33, maintains the cardioprotective effects of relaxin and more rapidly reduces left ventricular fibrosis compared to perindopril in an experimental model of cardiomyopathy

The single-chain relaxin mimetic, B7-33, maintains the cardioprotective effects of relaxin and more rapidly reduces left ventricular fibrosis compared to perindopril in an experimental model of cardiomyopathy

  • Biomed Pharmacother. 2023 Feb 6;160:114370. doi: 10.1016/j.biopha.2023.114370.
Fariha Alam 1 Tracey A Gaspari 1 Barbara K Kemp-Harper 1 Edward Low 1 Aaron Aw 1 Dorota Ferens 1 Iresha Spizzo 1 Ann-Maree Jefferis 1 Praveen Praveen 2 Robert E Widdop 1 Ross A D Bathgate 3 Mohammed Akhter Hossain 4 Chrishan S Samuel 5
Affiliations

Affiliations

  • 1 Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
  • 2 Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
  • 3 Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia; Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
  • 4 Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia; School of Chemistry, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: akhter.hossain@unimelb.edu.au.
  • 5 Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: chrishan.samuel@monash.edu.
Abstract

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.

Keywords

ACE inhibitor; Cardiomyopathy; LV, fibrosis; Relaxin, B7–33.

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