Spermidine attenuates left ventricular dysfunction in estrogen deprived aging rats through mitigating lipid peroxidation and mitochondrial dysfunction

Abstract

Abstract Background Aging women with postmenopause are particularly susceptible to cardiovascular diseases (CVDs), which are associated with the elevation of oxidative stress and mitochondrial dysfunction. Although hormone replacement therapy (HRT) has been reported to provide cardiometabolic protection, long-term HRT could be linked to CVD consequences. A novel organic therapy with spermidine has shown promise as cardioprotection in several CVDs. However, the effects of spermidine on left ventricular (LV) function, mitochondrial function and oxidative stress in estrogen-deprived aging rats have not been investigated. Purpose To evaluate the effects of spermidine on LV function, mitochondrial function and oxidative stress in estrogen-deprived and D-galactose-induced aging rats Methods Twenty female Wistar rats were randomly assigned to the sham and the ovariectomy (OVX) along with D-galactose (150 mg/kg/day, s.c.) administration throughout the experiment for 12 weeks. OVX with D-galactose-treated rats were divided into three interventional groups: vehicle (ODV), spermidine (20 mg/kg/day, p.o., ODS), and estradiol (50 ug/kg/day, s.c., ODE) (n=5/group) for 8 weeks. The sham group received a vehicle (SVV, n=5). At the end, all rats underwent echocardiography, followed by euthanasia. The hearts were removed for measuring mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) changes (ΔΨm), and malondialdehyde (MDA) levels. Results Rats with OVX-induced estrogen deprivation with D-galactose-induced aging had LV impairments indicated by decreased LV ejection fraction, reduced ratio of peak velocity blood flow from left ventricular relaxation in early diastole (E) to peak velocity flow by atrial contraction (A), and increased sympathovagal imbalance (elevated low/high frequency (LF/HF) ratio) (Fig. 1A-C). These estrogen-deprived aging rats also had an increase in cardiac tissue MDA levels, mitochondrial ROS production, and MMP depolarization (Fig. 1D-F). Both spermidine and estrogen similarly demonstrated a significant reduction in all of those detrimental effects, leading to improved LV function (Fig. 1A-F). Conclusion Spermidine exerted cardioprotection comparable to estrogen supplement through mitigating oxidative stress and mitochondrial impairments in cardiac tissue, resulting in improved LV dysfunction and cardiac autonomic balance due to estrogen deprived aging conditions in rats. These findings suggest that spermidine administration could be a promising strategy for cardioprotection in postmenopausal women with aging.