School of Physiology (ETDs)

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    The effect of circadian misalignment on cardiometabolic parameters in a rat model of estrogen deficiency
    (University of the Witwatersrand, Johannesburg, 2024) Nthlane, Refentshe Amandu’s; Michel, Frédéric
    Menopausal women engaging in shift work are at an increased risk of cardiometabolic disorders (CMD). The increased risk is due to the dual impact of menopause-associated estrogen withdrawal and the shiftwork-induced irregular light exposure, which disrupts circadian rhythms, leading to chronic circadian misalignment. However, the combination of circadian misalignment related to shift work and menopause on cardiometabolic health remains poorly understood. Therefore, the present study aimed to determine whether circadian misalignment worsens cardiometabolic parameters in estrogen-deficient female spontaneously hypertensive rats (SHR). Circadian misalignment was induced by a 10-week chronic phase shift (CPS) protocol, and estrogen deficiency was induced by ovariectomy. Thirty-six female SHR were ovariectomized or sham- operated 7 weeks after birth, and then subjected to a CPS or control lighting (ctr light) schedule (n=9 per group). Body mass, food and water intake, blood pressure and fasting blood glucose concentrations were measured throughout the 10-week protocol. An oral glucose tolerance test was performed 3 days before the end of the 10-week protocol, while ventricular systolic and diastolic function were assessed by echocardiography at the end of the 10-week protocol. Organ mass was measured, and LDL concentration was determined from collected serum with ELISA. Ovariectomized rats were heavier than sham-operated rats overtime (211 ± 38 vs. 169 ± 22g; p <0.0001). Food intake and organ masses were greater in ovariectomized rats compared to the sham-operated rats. When normalized to body mass, the food intake and organ masses were lower than in the sham-operated rats. Ovariectomized rats had greater left ventricular (LV) end-diastolic diameter (5.1 ± 0.4 vs. 4.6 ± 0.6mm; p = 0.03) and LV end-systolic diameter (3.0 ± 0.5 vs. 2.4 ± 0.4mm; p = 0.004) than sham-operated rats. The ovariectomized rats also had reduced endocardial fractional shortening (41 ± 8 vs. 49 ± 4%) and LV ejection fraction (71 ± 10 vs. 80 ± 4%) (both p = 0.007) than sham-operated rats. The cardiometabolic parameters measured were similar between the CPS and control lighting rats, except for a greater water intake overtime (CPS: 29 ± 7.1 vs. ctr light: 26 ± 3.2ml/day; p = 0.048) and a reduced liver mass (CPS: 7.2 ± 0.6 vs. ctr light: 7.6 ± 0.8g; p = 0.03) in CPS rats. When normalized to body mass, sham-operated rats had a greater water intake than the ovariectomized rats. No interaction between ovariectomy and CPS was demonstrated. In conclusion, estrogen deficiency impairs systolic function in female SHR. However, circadian misalignment does not worsen the cardiometabolic parameters in female SHR. Because of their genetic predispositions, female SHR may already have abnormal circadian rhythms, illustrating the complex and multifaceted circadian regulation within this rat model