Hayward Grant C, LeBlanc Paul J, Emter Craig A, Nyarko Jennifer N K, Mousseau Darrell D, MacPherson Rebecca E K, Olver T Dylan
Department of Health Sciences, Brock University, St. Catharines, ON, Canada.
Centre for Neuroscience, Brock University, St. Catharines, ON, Canada.
Front Cardiovasc Med. 2019 Sep 10;6:129. doi: 10.3389/fcvm.2019.00129. eCollection 2019.
Post-menopausal women with heart failure (HF) frequently exhibit cardiogenic dementia. Using a pre-clinical swine model of post-menopausal HF, we recently demonstrated that experimental menopause (ovariectomy; OVX) and HF (6-month cardiac pressure overload/aortic banding; AB) independently altered cerebral vasomotor control and together impaired cognitive function. The purpose of this study was to examine the prefrontal cortex and hippocampus tissues from these animals to assess whether OVX and HF are associated with neurologic alterations that may contribute to cardiogenic dementia. We hypothesized that OVX and HF would independently alter neuronal cell signaling in swine with post-menopausal cardiogenic dementia. Immunoblot analyses revealed OVX was associated with reduced estrogen receptor-α in both brain regions and HF tended to exacerbate OVX-induced deficits in the hippocampus. Further, OVX was associated with a reduction in the ratio of phosphorylated:total Akt and ERK in the hippocampus as well as decreased total Akt and synaptophysin in the prefrontal cortex. In contrast, HF was associated with a trend toward reduced phosphorylated:total ERK in the prefrontal cortex. In addition, HF was associated with decreased β-amyloid (1-38) in the prefrontal cortex and increased β-amyloid (1-38) in the hippocampus. Regional brain lipid analysis revealed OVX tended to increase total, saturated, and monounsaturated fatty acid content in the prefrontal cortex, with the greatest magnitude of change occurring in the AB-OVX group. The data from this study suggest that OVX and HF are independently associated with regional-specific neurologic changes in the brain that contribute to the cardiogenic dementia profile in this model. This pre-clinical swine model may be a useful tool for better understanding post-menopausal cardiogenic dementia pathology and developing novel therapies.
绝经后心力衰竭（HF）女性常表现出心源性痴呆。我们最近利用绝经后HF的临床前猪模型证明，实验性绝经（卵巢切除术；OVX）和HF（6个月心脏压力超负荷/主动脉缩窄；AB）分别改变了脑血管舒缩控制，二者共同损害了认知功能。本研究的目的是检查这些动物的前额叶皮质和海马组织，以评估OVX和HF是否与可能导致心源性痴呆的神经学改变有关。我们假设OVX和HF会分别改变绝经后心源性痴呆猪的神经元细胞信号传导。免疫印迹分析显示，OVX与两个脑区雌激素受体-α减少有关，HF往往会加剧OVX诱导的海马区缺陷。此外，OVX与海马区磷酸化Akt与总Akt及ERK的比例降低以及前额叶皮质总Akt和突触素减少有关。相比之下，HF与前额叶皮质磷酸化ERK与总ERK的比例降低趋势有关。此外，HF与前额叶皮质β-淀粉样蛋白（1-38）减少及海马区β-淀粉样蛋白（1-38）增加有关。脑区脂质分析显示，OVX往往会增加前额叶皮质的总脂肪酸、饱和脂肪酸和单不饱和脂肪酸含量，AB-OVX组的变化幅度最大。本研究数据表明，OVX和HF分别与大脑区域特异性神经学变化有关，这些变化导致了该模型的心源性痴呆特征。这种临床前猪模型可能是更好地理解绝经后心源性痴呆病理和开发新疗法的有用工具。
