Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America.
Department of Biology, East Carolina University, Greenville, NC 27858, United States of America.
Life Sci. 2023 Oct 15;331:122038. doi: 10.1016/j.lfs.2023.122038. Epub 2023 Aug 22.
Estrogen (E2) confers cardioprotection in premenopausal women and in models of menopause and its effects, mostly studied in female reproductive organs, vary on a circadian rhythm basis in relation to the circadian clock genes. However, it remains unknown if a similar circadian pattern exists in the female heart in a manner that explains, at least partly, the cardioprotective effect of E2. The aim of the present investigation was to determine if upregulation of the circadian clock Per2 and its regulated heart-specific miRNAs, and redox enzymes contribute to the E2-mediated cardioprotection in ovariectomized rats.
Rats were subjected to ovariectomy (OVX) 2-weeks prior to a 2-week E2 treatment. On the last treatment day, hearts were collected every 4 h. for ex-vivo biochemical measurements. In parallel studies, telemetric mean arterial pressure (MAP) was obtained at the tissue collection times.
OVX + E2 rats exhibited lower body weight during daytime and MAP during day and night times, and their hearts exhibited: (1) higher Per2 protein abundance, cardioprotective miRNAs (miRNA1, miRNA133a, miRNA208a, miRNA499), mALDH2, and catalase; (2) lower reactive oxygen species, cardio-detrimental miRNA652, carbonyl, MDA and HO-1 levels. The reciprocal Per2/HO-1 relationship was more evident during the daytime and correlated with the upregulated cardioprotective miRNAs in OVX + E2 rats. Finally, cardiac Per2, heart-specific miRNAs and reactive oxygen species levels and redox enzymes activities were similar in normal female and OVX + E2 rats.
Enhancement of cardiac Per2, redox enzymes and heart-specific miRNAs likely contribute to E2-mediated mitigation of cardiac oxidative stress in OVX rats.
雌激素（E2）在绝经前女性和绝经模型中具有心脏保护作用，其作用主要在雌性生殖器官中进行研究，根据昼夜节律基因的变化，其作用在昼夜节律的基础上发生变化。然而，目前尚不清楚在女性心脏中是否存在类似的昼夜节律模式，这种模式至少部分解释了 E2 的心脏保护作用。本研究旨在确定昼夜节律钟 Per2 的上调及其调节的心脏特异性 miRNA 和氧化还原酶是否有助于去卵巢大鼠的 E2 介导的心脏保护作用。
大鼠在进行卵巢切除术（OVX）前 2 周进行 OVX，然后进行 2 周的 E2 治疗。在最后一次治疗日，每隔 4 小时收集心脏进行离体生化测量。在平行研究中，在组织收集时间获得遥测平均动脉压（MAP）。
OVX+E2 大鼠在白天的体重和白天和夜间的 MAP 较低，其心脏表现为：（1）更高的 Per2 蛋白丰度、心脏保护性 miRNA（miRNA1、miRNA133a、miRNA208a、miRNA499）、mALDH2 和过氧化氢酶；（2）更低的活性氧、心脏损害性 miRNA652、羰基、MDA 和 HO-1 水平。昼夜节律钟 Per2/HO-1 的这种相互关系在白天更为明显，并且与 OVX+E2 大鼠中上调的心脏保护性 miRNA 相关。最后，正常雌性和 OVX+E2 大鼠的心脏 Per2、心脏特异性 miRNA 和活性氧水平以及氧化还原酶活性相似。
增强心脏 Per2、氧化还原酶和心脏特异性 miRNA 可能有助于 E2 介导的减轻 OVX 大鼠心脏氧化应激。
