Cardiovascular (CV) disease is the major cause of mortality. Estrogens (E) exert multiple CV and neuroprotective effects. During menopause, CV and cognitive pathologies increase dramatically. At present, it is known that E exert many of their beneficial effects through the G protein-coupled estrogen receptor (GPER). Exercise reduces the risk of developing CV diseases. Sodium/proton exchanger (NHE-1) is overexpressed in ovariectomized (OVX) rats, probably due to the increase in reactive oxidative species (ROS). Insulin-like growth factor 1 (IGF-1), the main humoral mediator of exercise, inhibits the NHE-1. We aim to explore the subcellular mechanisms involved in the heart and brain impact of physiological exercise in OVX rats. We speculate that physical training, via IGF-1, prevents the increase in ROS, improving heart and brain physiological functions during menopause. Exercise diminished cardiac ROS production and increased catalase (CAT) activity in OVX rats. In concordance, IGF-1 treatment reduces brain ROS, surely contributing to the improvement in brain behavior. Moreover, the aerobic routine was able to prevent, and IGF-1 therapy to revert, NHE-1 hyperactivity in OVX rats. Finally, our results confirm the proposed signaling pathway as IGF-1/PI3K-AKT/NO. Surprisingly, GPER inhibitor (G36) was able to abolish the IGF-1 effect, suggesting that directly or indirectly GPER is part of the IGF-1 pathway. We propose that IGF-1 is the main responsible for the protective effect of aerobic training both in the heart and brain in OVX rats. Moreover, we showed that not only it is possible to prevent but also to revert the menopause-induced NHE-1 hyperactivity by exercise/IGF-1 cascade.

心血管 （CV） 疾病是导致死亡的主要原因。雌激素 （E） 发挥多种 CV 和神经保护作用。在更年期期间，CV 和认知病理急剧增加。目前，已知 E 通过 G 蛋白偶联雌激素受体 （GPER） 发挥许多有益作用。运动可降低患 CV 疾病的风险。钠/质子交换剂 （NHE-1） 在卵巢切除 （OVX） 大鼠中过表达，可能是由于活性氧化物质 （ROS） 的增加。胰岛素样生长因子 1 （IGF-1） 是运动的主要体液介质，可抑制 NHE-1。我们旨在探索参与 OVX 大鼠生理运动对心脏和大脑影响的亚细胞机制。我们推测，通过 IGF-1 进行体育锻炼可以防止 ROS 增加，从而改善更年期的心脏和大脑生理功能。运动减少了 OVX 大鼠的心脏 ROS 产生并增加了过氧化氢酶 （CAT） 活性。同时，IGF-1 治疗可降低大脑 ROS，肯定有助于改善大脑行为。此外，有氧运动能够预防 OVX 大鼠的 NHE-1 多动症，并且 IGF-1 疗法能够逆转 NHE-1 多动症。最后，我们的结果证实了提出的信号通路为 IGF-1/PI3K-AKT/NO。令人惊讶的是，GPER 抑制剂 （G36） 能够消除 IGF-1 效应，表明 GPER 直接或间接是 IGF-1 通路的一部分。我们提出 IGF-1 是 OVX 大鼠心脏和大脑中有氧训练保护作用的主要负责人。此外，我们表明不仅可以预防而且可以通过运动/IGF-1 级联来恢复更年期诱导的 NHE-1 多动症。