Long-term spermidine therapy potentially protects the heart against estrogen deprivation in female rats via suppressing cardiac mitochondrial dysfunction, inflammation, oxidative stress, and apoptosis

Abstract Background Postmenopausal women have been associated with a higher risk of cardiovascular diseases (CVDs). Several pathophysiological mechanisms, including cardiac mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte apoptosis, played a key role in the development of postmenopausal CVDs. Long-term estrogen supplementation is widely used to treat postmenopausal symptoms, but it has been linked to an increased risk of breast cancer and cardiac complications. Spermidine is a natural organic compound which has been shown to exert cardioprotection under several pathological conditions. However, the benefits of spermidine against impaired cardiac function due to estrogen-deprivation are unknown. Purpose To investigate the effects of therapeutic intervention with spermidine on cardiac mitochondrial function, oxidative stress, inflammation, and programmed cardiomyocyte death in rats with estrogen deprivation. Methods Fifteen female Wistar rats underwent ovariectomy (OVX) to induce estrogen deprivation. After 12 weeks, all OVX-operated rats were randomly divided into three interventional groups as follows: 1) vehicle or OV (n = 5), 2) spermidine or OS (20 mg/kg/day, p.o., n = 5), and 3) estradiol or OE (50 µg/kg/day, s.c., n = 5) for an additional 8 weeks. At the end of the experiment, echocardiography for the heart’s function was performed. Then, all the rats were sacrificed, and their hearts were dissected for mitochondrial and molecular analysis, including the protein expressions of inflammation, oxidative stress, and apoptosis. Results Treatment with either spermidine or estrogen provided a similar cardioprotective efficacy against OVX-induced estrogen deprivation in reducing mitochondrial membrane potential depolarization and cardiac inflammation, as shown by increased red to green fluorescence and lowered p-NFkB to NFkB ratios, respectively (Fig. 1A, B). Spermidine and estrogen also exerted anti-oxidative stress via increasing glutathione peroxidase (GPX4) and anti-apoptosis via decreasing the cleaved caspase-3 to procaspase-3 ratio following OVX-induced estrogen deficiency (Fig. 1C, D). All of the beneficial effects of spermidine and estrogen led to an improved left ventricular ejection fraction (89% for OS and OE vs. 76% for OV). Conclusion Long-term treatment with spermidine rescued cardiac mitochondrial dysfunction, inflammation, oxidative stress, and apoptosis, resulting in the restoration of left ventricular function with the same efficacy as estrogen treatment. These findings suggest that spermidine could be a novel therapeutic strategy to alleviate the adverse cardiac complications associated with postmenopausal women.