BRCA1在慢性间歇性低氧所致心脏损伤中的作用及其机制的研究

Obstructive sleep apnea (OSA) is the most common type of sleep-disorderedbreathing. Chronic intermittent hypoxia (CIH) is considered to be the main event of OSA to induce cardiac damage. Our preliminary studies showed that (1) Endogenous metallothionein (MT) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression was up-regulated with no obviously cardiac damage in response to early stage of CIH, but significantly decreased with significantly cardiac oxidative damage, remodeling and dysfunction in response to late stage of CIH exposures, the changes of cardiac BRCA1 expression was in parallel with MT and Nrf2 expression; (2) In support of MT and Nrf2 as a major compensatory component, mice with cardiac-specific overexpression of MT gene (MT-TG) and cardiac-specific overexpression of Nrf2 (Nrf2-TG) were completely resistant and mice with global deletion of MT gene (MT-KO) and global deletion of Nrf2 (Nrf2-KO) were highly sensitive to CIH-induced cardiac effects, respectively. (3) Reciprocal regulation of cardiac Nrf2 and MT expressions in response to IH. In this study, therefore, we will interbreed BRCA1-KO mice, in combination of Nrf2-KO and MT-KO mouse models, to investigate CIH-induced cardiac damage. The objective of this study is to define the role of BRCA1 in CIH-induced cardiac damage and dissect whether BRCA1 as a compensatory component prevents intermittent hypoxia-induced cardiomyopathy and the relationship among BRCA1, Nrf2 and MT. We explored the whether SFN can protect IH-induced cardiomyopathy without BRCA1.

呼吸睡眠暂停(OSA)是常见的睡眠呼吸疾病，OSA模式的慢性间歇性低氧(CIH)是引发心脏损伤的主要原因。前期工作中我们发现：①CIH条件下，小鼠心肌组织BRCA1的表达与金属硫蛋白(MT）和NF-E2相关因子2 (Nrf2）相同，均呈现早期升高、晚期下降的趋势；②MT过表达转基因(MT-TG)和 Nrf2-TG小鼠保护CIH所致的心肌损伤，而MT基因敲除(MT-KO)和Nrf2-KO小鼠使损伤提前出现且程度加重；③CIH条件下MT与Nrf2相互协同作用。本课题拟通过构建BRCA1心脏特异性基因敲除(BRCA1-KO)小鼠，同时应用Nrf2-KO和MT-KO小鼠，阐明BRCA1在CIH所致心脏损伤中的作用并探讨BRCA1、Nrf2和MT之间的关系及相关机制，同时应用Nrf2激动剂莱菔硫烷(SFN)，明确其是否可挽救BRCA1基因突变所加重的CIH所致的心脏损伤。

阻塞性睡眠呼吸暂停（obstructive sleep apnea, OSA）低通气综合征，是一种最常见的严重危害人类健康的睡眠疾病之一。慢性间歇性低氧（chronic intermittent hypoxia, CIH）是OSA的主要病理特征，目前众多学者应用CIH的动物模型研究OSA所致的心脏损伤，发现CIH是引发包括心室重构在内的心脏损伤的主要原因。目前认为，氧化应激是OSA所致心血管疾病的主要发病机制之一。前期工作中我们发现：①CIH条件下，小鼠心肌组织BRCA1的表达与金属硫蛋白(MT）和NF-E2相关因子2 (Nrf2）相同，均呈现早期升高、晚期下降的趋势；②MT过表达转基因(MT-TG)和 Nrf2-TG小鼠保护CIH所致的心肌损伤，而MT基因敲除(MT-KO)和Nrf2-KO小鼠使损伤提前出现且程度加重 ③CIH条件下MT与Nrf2相互协同作用。我们研究发现BRCA1与MT和Nrf2之间存在协同作用，在CIH所致心脏损伤中发挥作用，并且发现SFN在CIH所致心脏损伤中发挥保护作用，并且这一保护作用依赖Nrf2的存在。