Epigenetic gene expression links heart failure to memory impairment.
Epigenetic gene expression links heart failure to memory impairment.
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DOI：
10.15252/emmm.201911900
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发表时间：
2021-03-05
影响因子：
11.1
通讯作者：
Fischer A
中科院分区：
文献类型：
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作者：
Islam MR;Lbik D;Sakib MS;Maximilian Hofmann R;Berulava T;Jiménez Mausbach M;Cha J;Goldberg M;Vakhtang E;Schiffmann C;Zieseniss A;Katschinski DM;Sananbenesi F;Toischer K;Fischer A
在当前的临床实践中，对患病患者的护理通常限于单独的学科。然而，这种以器官为中心的方法并不总是合适的。例如，认知功能障碍是心力衰竭患者的严重负担。此外，这些患者患年龄相关性痴呆的风险增加。其潜在的分子机制目前尚不清楚，因此，缺乏改善心力衰竭患者认知的相应治疗策略。以小鼠为模型生物，我们发现心力衰竭导致海马基因表达的特定变化，海马是与认知密切相关的大脑区域。这些变化反映了细胞应激途径的增加，最终导致神经元常染色质的丢失和认知所必需的海马基因簇的表达减少。因此，患有心力衰竭的小鼠表现出受损的记忆功能。这些病理变化通过给予促进神经元常染色质形成的药物而得到改善。我们的研究首次揭示了心力衰竭导致神经元功能障碍的分子过程，并指出了治疗心力衰竭患者认知缺陷的新治疗途径。患有心力衰竭的患者发生年龄相关性痴呆的风险增加。这项研究阐明了潜在的机制，并提供证据表明心力衰竭诱导的认知能力下降与影响神经元基因表达的表观遗传变化有关。
In current clinical practice, care of diseased patients is often restricted to separated disciplines. However, such an organ‐centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age‐associated dementias. The underlying molecular mechanisms are presently unknown, and thus, corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms, we show that heart failure leads to specific changes in hippocampal gene expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients. Patients suffering from heart failure have an increased risk to develop age‐associated dementia. This study elucidates the underlying mechanisms and provides evidence that heart‐failure induced cognitive decline is linked to epigenetic changes that affect neuronal gene expression.