Brain and Heart Research Group, University of Ottawa Heart Institute , Ottawa, Ontario , Canada.
Department of Cellular and Molecular Medicine and Neuroscience Program, University of Ottawa Brain and Mind Institute , Ottawa, Ontario , Canada.
Am J Physiol Heart Circ Physiol. 2018 Nov 1;315(5):H1159-H1173. doi: 10.1152/ajpheart.00615.2017. Epub 2018 Jul 27.
Patients with heart failure (HF) have a high prevalence of depression associated with a worse prognosis, particularly in older women. The present study evaluated whether sex and estrogens affect depression-like behavior and associated neuroinflammation induced by myocardial infarction (MI) in rats. MI was induced by occlusion of the left anterior descending artery in young adult male and female Wistar rats or in ovariectomized (OVX) female rats without and with estrogen [17β-estradiol (E)] replacement. MI groups showed a comparable degree of cardiac dysfunction. Eight weeks post-MI, male rats with HF exhibited depression-like behaviors, including anhedonia and higher immobility in the sucrose preference and forced swim tests, which were not observed in female rats with HF. In the cued fear conditioning test, male but not female rats with HF froze more than sham rats. After OVX, female sham rats developed mild depression-like behaviors that were pronounced in OVX female rats post-MI and were largely prevented by E replacement. Cytokine levels in the plasma and paraventricular nucleus increased in both sexes with HF, but only male rats with HF showed an increase in cytokine levels in the prefrontal cortex. OVX alone did not affect cytokine levels, but OVX-MI caused significant increases in the prefrontal cortex, which were shifted to an anti-inflammatory pattern by E replacement. These results suggest that estrogens prevent depression-like behavior induced by HF post-MI in young adult female rats by inhibiting proinflammatory cytokine production and actions in the prefrontal cortex. NEW & NOTEWORTHY In contrast to male rats, female rats with heart failure after myocardial infarction do not develop depression-like behavior or increases in prefrontal cortex cytokines. However, after ovariectomy, female rats exhibit similar changes, which are prevented by 17β-estradiol replacement. Neuroinflammation in the prefrontal cortex in male subjects may contribute to depression-like behavior, whereas its estrogen-dependent absence in female subjects may protect against depression.
心力衰竭（HF）患者常伴有抑郁，其预后较差，尤其是老年女性。本研究评估了性别和雌激素是否会影响心肌梗死（MI）诱导的大鼠抑郁样行为和相关神经炎症。通过结扎左前降支动脉在年轻成年雄性和雌性 Wistar 大鼠或去卵巢（OVX）雌性大鼠中诱导 MI，并且有无雌激素[17β-雌二醇（E）]替代。MI 组表现出相当程度的心脏功能障碍。MI 后 8 周，HF 雄性大鼠表现出抑郁样行为，包括快感缺失和蔗糖偏好和强迫游泳试验中更高的不动性，而 HF 雌性大鼠则没有观察到。在条件性恐惧测试中，HF 雄性大鼠比假手术大鼠更易冻结。OVX 后，雌性假手术大鼠出现轻度抑郁样行为，MI 后 OVX 雌性大鼠更为明显，而 E 替代则很大程度上预防了这种行为。HF 后两种性别血浆和室旁核中的细胞因子水平均升高，但只有 HF 雄性大鼠的前额叶皮质中的细胞因子水平升高。OVX 本身不会影响细胞因子水平，但 OVX-MI 导致前额叶皮质中的细胞因子水平显著增加，而 E 替代则将其转变为抗炎模式。这些结果表明，雌激素通过抑制前额叶皮质中促炎细胞因子的产生和作用，预防年轻成年雌性大鼠 MI 后 HF 诱导的抑郁样行为。
