TY - JOUR
T1 - 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
AU - Alam, Fariha
AU - Gaspari, Tracey A.
AU - Kemp-Harper, Barbara K.
AU - Low, Edward
AU - Aw, Aaron
AU - Ferens, Dorota
AU - Spizzo, Iresha
AU - Jefferis, Ann-Maree
AU - Praveen, Praveen
AU - Widdop, Robert E.
AU - Bathgate, Ross A.D.
AU - Hossain, Mohammed Akhter
AU - Samuel, Chrishan S.
N1 - Funding Information:
This work was supported by a National Health & Medical Research Council (NHMRC) of Australia Project Grant ( GNT2001278 ) to M.A. Hossain and C.S. Samuel; a NHMRC Senior Research Fellowship to R.A.D. Bathgate ( GNT1135837 ); and a Monash Biomedicine Discovery Institute Senior Research Fellowship to C.S. Samuel. Studies at the Florey Institute were supported by the Victorian Government’s Operational Infrastructure Support Program .
Publisher Copyright:
© 2023 The Authors
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
KW - ACE inhibitor
KW - Cardiomyopathy
KW - LV, fibrosis
KW - Relaxin, B7–33
UR - http://www.scopus.com/inward/record.url?scp=85147360617&partnerID=8YFLogxK
U2 - 10.1016/j.biopha.2023.114370
DO - 10.1016/j.biopha.2023.114370
M3 - Article
C2 - 36753958
AN - SCOPUS:85147360617
SN - 0753-3322
VL - 160
JO - Biomedicine & Pharmacotherapy
JF - Biomedicine & Pharmacotherapy
M1 - 114370
ER -