小柯机器人

美国哥伦比亚大学Andrew R. Marks研究团队发现，心衰(HF)诱导的认知功能障碍(CD)是通过ryanodine受体2型(RyR2)介导的细胞内Ca2+泄漏。该项研究成果发表在2023年7月10日出版的《自然—神经科学》上。

他们发现在HF个体和小鼠的海马神经元中，RyR2/细胞内Ca2+释放通道受到翻译后修饰(PTM)的影响，并且是泄漏的。RyR2 PTM包括蛋白激酶A磷酸化、氧化、亚硝基化和稳定亚基钙稳定蛋白2的缺失。RyR2 PTM是由高肾上腺素能信号和转化生长因子- β通路的激活引起的。用RyR2稳定剂(S107)、β受体阻滞剂(普pranolol)，或转化生长因子- β抑制剂(SD-208)，或抗RyR2 Ca2+泄漏(RyR2-p. Ser2808 Ala)的基因工程小鼠治疗HF小鼠，可防止HF诱导的CD。综上所述，他们提出HF是一种由细胞内Ca2+泄漏驱动的全体性疾病，包括心源性痴呆。

据悉，HF患者的CD对治疗依从性和生活质量有不利影响。虽然RyR2与心肌功能障碍有关，但其在HF患者CD中的作用尚不清楚。

附：英文原文

Title: Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through ryanodine receptor type 2

Author: Dridi, Haikel, Liu, Yang, Reiken, Steven, Liu, Xiaoping, Argyrousi, Elentina K., Yuan, Qi, Miotto, Marco C., Sittenfeld, Leah, Meddar, Andrei, Soni, Rajesh Kumar, Arancio, Ottavio, Lacampagne, Alain, Marks, Andrew R.

Issue&Volume: 2023-07-10

Abstract: Cognitive dysfunction (CD) in heart failure (HF) adversely affects treatment compliance and quality of life. Although ryanodine receptor type 2 (RyR2) has been linked to cardiac muscle dysfunction, its role in CD in HF remains unclear. Here, we show in hippocampal neurons from individuals and mice with HF that the RyR2/intracellular Ca2+ release channels were subjected to post-translational modification (PTM) and were leaky. RyR2 PTM included protein kinase A phosphorylation, oxidation, nitrosylation and depletion of the stabilizing subunit calstabin2. RyR2 PTM was caused by hyper-adrenergic signaling and activation of the transforming growth factor-beta pathway. HF mice treated with a RyR2 stabilizer drug (S107), beta blocker (propranolol) or transforming growth factor-beta inhibitor (SD-208), or genetically engineered mice resistant to RyR2 Ca2+ leak (RyR2-p.Ser2808Ala), were protected against HF-induced CD. Taken together, we propose that HF is a systemic illness driven by intracellular Ca2+ leak that includes cardiogenic dementia.

DOI: 10.1038/s41593-023-01377-6

Source: https://www.nature.com/articles/s41593-023-01377-6

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex