AIMS To investigate if autonomic dysregulation is exacerbated in female rats, subjected to diabetes mellitus (DM), via a paradoxical estrogen (E2)-evoked provocation of neuroinflammation/injury of the hypothalamic paraventricular nucleus (PVN). MAIN METHODS We measured cardiac autonomic function and conducted subsequent PVN neurochemical studies, in DM rats, and their respective controls, divided as follows: male, sham operated (SO), ovariectomized (OVX), and OVX with E2 supplementation (OVX/E2). KEY FINDINGS Autonomic dysregulation, expressed as sympathetic dominance (higher low frequency, LF, band), only occurred in DM E2-replete (SO and OVX/E2) rats, and was associated with higher neuronal activity (c-Fos) and higher levels of TNFα and phosphorylated death associated protein kinase-3 (p-DAPK3) in the PVN. These proinflammatory molecules likely contributed to the heightened PVN oxidative stress, injury and apoptosis. The PVN of these E2-replete DM rats also exhibited upregulations of estrogen receptors, ERα and ERβ, and proinflammatory adenosine A1 and A2a receptors. SIGNIFICANCE The E2-dependent autonomic dysregulation likely predisposes DM female rats and women to hypersensitivity to cardiac dysfunction. Further, upregulations of proinflammatory mediators including adenosine A1 and A2 receptors, TNFα and DAPK3, conceivably explain the paradoxical hypersensitivity of DM females to PVN inflammation/injury and the subsequent autonomic dysregulation in the presence of E2.

中文翻译：

---

雌激素依赖性超敏反应对糖尿病引起的心脏自主神经失调：下丘脑神经炎症的作用。


目的 调查患有糖尿病 (DM) 的雌性大鼠的自主神经失调是否会通过矛盾的雌激素 (E2) 诱发下丘脑室旁核 (PVN) 的神经炎症/损伤而加剧。主要方法 我们测量了 DM 大鼠及其各自对照的心脏自主功能并进行了随后的 PVN 神经化学研究，分为：雄性、假手术 (SO)、卵巢切除 (OVX) 和补充 E2 的 OVX (OVX/E2) 。主要发现 自主神经失调，表现为交感神经支配（较高的低频、LF、频带），仅发生在 DM E2 充满的（SO 和 OVX/E2）大鼠中，并且与较高的神经元活动 (c-Fos) 和较高的水平相关PVN 中 TNFα 和磷酸化死亡相关蛋白激酶 3 (p-DAPK3) 的变化。这些促炎分子可能导致 PVN 氧化应激、损伤和细胞凋亡加剧。这些 E2 充足的 DM 大鼠的 PVN 还表现出雌激素受体 ERα 和 ERβ 以及促炎腺苷 A1 和 A2a 受体的上调。意义 E2 依赖性自主神经失调可能使 DM 雌性大鼠和女性对心功能不全过敏。此外，促炎介质（包括腺苷 A1 和 A2 受体、TNFα 和 DAPK3）的上调可以解释 DM 女性对 PVN 炎症/损伤的矛盾超敏反应以及随后 E2 存在下的自主神经失调。