Simultaneous targeting of oxidative stress and fibrosis reverses cardiomyopathy‐induced ventricular remodelling and dysfunction

Abstract

Background and Purpose: Oxidative stress and fibrosis are hallmarks of cardiomyopathy-induced heart failure yet are not effectively targeted by current frontline therapies. Here, the therapeutic effects of the anti-oxidant, N-acetylcysteine (NAC), were compared and combined with an acute heart failure drug with established anti-fibrotic effects, serelaxin (RLX), in a murine model of cardiomyopathy.Experimental Approach: Adult male 129sv mice were subjected to repeated isoprenaline (25 mgÁkg −1 )-induced cardiac injury for five consecutive days and then left to undergo fibrotic healing until Day 14. Subgroups of isoprenaline-injured mice were treated with RLX (0.5 mgÁkg −1 Áday −1 ), NAC (25 mgÁkg −1 Áday −1 ) or both combined, given subcutaneously via osmotic minipumps from Day 7 to 14. Control mice received saline instead of isoprenaline.

Relaxin Inhibits the Cardiac Myofibroblast NLRP3 Inflammasome as Part of Its Anti-Fibrotic Actions via the Angiotensin Type 2 and ATP (P2X7) Receptors

“…The RLX-induced blunting of LV cardiomyocyte hypertrophy that was observed in this study is somewhat consistent with previous findings demonstrating that RLX (0.5 mg/kg/day) administration alone over a 7 day period did not have a marked impact on LV cardiomyocyte size in ISO-injured mice [37], but significantly reduced LV cardiomyocyte hypertrophy in a murine model of diabetic cardiomyopathy, when continuously administered at the same dose over a 14-day period [53] in vivo. Interestingly, whilst the antagonism of P2X7R activity alone (with A-438079) also only blunted LV cardiomyocyte size after 7 days of treatment in ISO-injured mice, 16 weeks of A438079 (10 or 20 mg/kg/day) administration to mice with diabetic cardiomyopathy prevented the disease-induced increase in the HW:BW ratio and measures of hypertrophic gene expression [54].…”

“…The administration of RLX and/or A4 treatment of ISO-injured mice (from days 7-14 postinjury) did not significantly affect SBP levels compared to the measurements for their saline-injected counterparts (Table 1). Consistent with previous studies [34,36,37], these findings confirmed that ISO induced fibrotic cardiomyopathy in mice, in the absence of any marked changes in SBP. Furthermore, these findings confirmed that the regulatory effects of RLX and/or A4 on measures of LV inflammation, remodelling and fibrosis were mediated independently of SBP regulation in the model studied.…”

“…To determine if the NLRP3-inhibitory and anti-fibrotic effects of RLX were mediated via the P2X7R in vivo, sub-groups of male 129 sv/ev mice were subcutaneously administered with ISO (25 mg/kg body weight) once daily for 5 consecutive days [34,36,37] and then were left for a further 9 days for left ventricular (LV) fibrosis to develop. Thereafter, mice were randomly assigned to the following groups and were either left untreated (ISO-injured control group; n = 7) or were treated at day 7 post-injury with either RLX alone (0.5 mg/kg/day, a dose previously used to demonstrate its therapeutic actions in ISO-injured mice in vivo [34,36,37] via s.c-implanted model 1007D osmotic mini-pumps; Alzet, Cupertino, CA, USA; n = 6), A-438079 (A4) alone (34.2 mg/kg/day, a dose used previously to demonstrate its P2X7R-inhibitory actions in vivo [47] via daily s.c-injections for 7 days; n = 6), or both RLX (0.5 mg/kg/day)+A4 (34.2 mg/kg/day) combined (n = 6). All treatments were maintained for a 7-day period, until day 14 post-injury.…”

“…Images of each section were sampled at ×40-400 magnification and then combined using the Image J software (NIH, Bethesda, MD, USA). In each case, images from 6-8 nonoverlapping fields were captured (at ×400 magnification) and analysed, and the data were expressed as the percentage of the fractional area of each end point stained [37].…”

Fibroblast growth factor 20 attenuates pathological cardiac hypertrophy by activating the SIRT1 signaling pathway

“…In our results, hypertrophic stimulation caused accumulation of ROS and subsequent apoptosis of cardiomyocytes; this finding is in agreement with previous studies [ 39 , 40 ]. Strategies to inhibit oxidative stress prevent the development of cardiomyopathy [ 41 , 42 ]. Research from Huang et al [ 43 ] revealed that FGF9, which shares 70% amino acid sequence similarity with FGF20, functioned as a protective factor by increasing the expression of antioxidant enzymes, which protected nigral dopaminergic neurons from MPP + -induced oxidative insult [ 34 ].…”