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Objectives: Postmenopausal women are at higher risk of metabolic syndrome and cardiovascular disease, which are aggravated by obesity. Although estrogen provides cardiometabolic protection, chronic high-dose treatment could be harmful. This study investigated the efficacy of combined N-acetylcysteine (NAC) and low-dose estrogen treatment against cardiometabolic dysfunction in female estrogen-deprived obese rats with cardiac ischemia-reperfusion (I/R) injury., Methods: Bilateral ovariectomized (O) female Wistar rats were fed a high-fat diet (H) for 12 weeks. Then, rats were treated for 4 weeks with one of the following: vehicle (OH; sesame oil), regular-dose estrogen (E; 50 μg/kg/d), low-dose estrogen (e; 25 μg/kg/d), NAC (N; 100 mg/kg/d), or combined low-dose estradiol with NAC (eN). All rats then underwent cardiac I/R injury, and the left ventricle (LV) function and mitochondrial function were investigated (n = 6/group). Statistical analysis was performed by one-way ANOVA followed by Fisher's least significant difference post hoc test., Results: Body weight, visceral fat, plasma glucose, and plasma cholesterol were significantly increased with impaired LV function and heart rate variability in OH rats. OH-E rats had decreased plasma insulin and Homeostatic Model Assessment for Insulin Resistance index. Both OH-E and OH-eN rats had similarly improved heart rate variability and LV function. During cardiac I/R, OH-E and OH-eN rats had preserved left ventricular ejection fraction, stroke volume, and attenuated arrhythmias. Impaired cardiac mitochondrial function and infarct size were similarly reduced in OH-E and OH-eN rats., Conclusions: Combined NAC and low-dose estrogen treatment shares similar efficacy as regular-dose estrogen in attenuating cardiac dysfunction, cardiac mitochondrial dysfunction, and protecting the heart against I/R injury in estrogen-deprived obese insulin-resistant rats., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2024 by The Menopause Society.)

Myocardial damage and mitochondrial dysfunction caused by cardiac ischemia-reperfusion (I/R) injury are intensified by endogenous estrogen deprivation. Although N-acetylcysteine (NAC) exerted cardioprotective effects, its benefits when used in combination with hormone therapy are unknown. We tested the hypothesis that a combination of NAC with low-dose estrogen improves cardiometabolic function and protects cardiac mitochondria against I/R injury, to a similar extent to regular-dose estrogen treatment, in estrogen-deprived rats. Female Wistar rats had a bilateral ovariectomy (OVX) or sham operation. Twelve weeks after the operation, OVX rats were treated with regular-dose estrogen (E; 50 µg/kg/day), low-dose estrogen (e; 25 µg/kg/day), NAC (N; 100 mg/kg/day) or combined low-dose estradiol with NAC (eN) for 4 weeks (n = 6/group). Metabolic parameters, echocardiography, heart rate variability and then cardiac I/R protocol involving 30-min coronary artery ligation, followed by 120-min reperfusion, were performed. OVX rats had increased body weight, visceral fat, fasting plasma glucose, HOMA-IR index, triglycerides, cholesterol and LDL levels (P < 0.05 vs sham). Only OVX-E and OVX-eN had a similarly improved HOMA-IR index. LVEF was increased in all treatment groups, but HRV was restored only by OVX-E and OVX-eN. After I/R, myocardial infarct size was decreased in both OVX-E and OVX-eN groups. OVX-E and OVX-eN rats similarly had a reduced mitochondrial ROS level and increased mitochondrial membrane potential in the ischemic myocardium. In conclusion, combined NAC with low-dose estrogen and regular-dose estrogen therapy similarly improve cardiometabolic function, prevent cardiac mitochondrial dysfunction and reduces the infarct size in estrogen-deprived rats with cardiac I/R injury.