Nrf2在金属硫蛋白保护慢性间歇性低氧所致心脏损伤中的作用

Obstructive sleep apnea (OSA) is the most common type of sleep-disordered breathing. Chronic intermittent hypoxia (CIH) is considered to be the main event of OSA to induce vetricular remodeling and cardiac damage, which mechanistically related to oxidative stress. Our preliminary studies showed that (1) Endogenous metallothionein (MT) expression was up-regulated with no obviously cardiac damage in response to 3-day CIH, but significantly decreased with significantly cardiac oxidative damage, remodeling and dysfunction in response to 4- and 8-week CIH exposures; (2) In support of MT as a major compensatory component, mice with cardiac-specific overexpression of MT gene (MT-TG) were completely resistant and mice with global deletion of MT gene (MT-KO) were highly sensitive to CIH-induced cardiac effects, respectively; (3) The changes of cardiac Nrf2 expression was in parallel with MT expression; and MT can regulate the expression of Nrf2. In this study, therefore, we will interbreed MT-TG-Nrf2-KO mice, in combination of Nrf2-KO, Nrf2-TG and MT-TG mouse models, to investigate CIH-induced cardiac damage. The objective of this study is to define the role of Nrf2 in CIH-induced cardiac damage and dissect whether metallothionein as a compensatory component prevents intermittent hypoxia-induced cardiomyopathy via Nrf2.

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)是引发包括心室重构在内的心脏损伤的主要原因，氧化应激是其主要发病机制之一。前期工作中我们发现① CIH 3天时小鼠心肌组织金属硫蛋白(MT)表达升高，心肌未见明显损伤，CIH 4周及8周时MT表达下降，出现心肌氧化应激损伤及心功能不全；②MT过表达转基因(MT-TG)小鼠保护CIH所致的心肌损伤而MT基因敲除(MT-KO)小鼠使损伤提前出现且程度加重；③CIH条件下，NF-E2相关因子2(Nrf2)的表达趋势与MT相同，且MT可调节Nrf2的表达。本课题拟通过构建MT心脏特异性过表达同时Nrf2基因敲除(MT-TG-Nrf2-KO)的双重转基因小鼠，同时应用Nrf2-KO、Nrf2-TG和MT-TG小鼠研究CIH所致的心脏损伤，阐明Nrf2在CIH所致心脏损伤中的作用并探讨MT的保护作用是否经由Nrf2介导。

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。我们在前期研究中发现CIH早期（3天）心肌组织未见明显氧化应激损伤同时伴随金属硫蛋白（metallothionein, MT）表达升高，然而在CIH晚期（4周和8周）MT表达下降、心肌氧化应激水平升高并出现心肌损伤及心功能下降；并且MT心脏特异性过表达转基因（cardiac-specific overexpressing MT gene, MT-TG）小鼠证实MT对CIH所致的心肌氧化应激损伤、心肌纤维化、炎症及心功能不全有明确的保护作用；与此同时MT基因敲除（MT-knockout, MT-KO）小鼠导致CIH诱导的心脏损伤提前出现并且程度加重。NF-E2相关因子2（NF-E2-related factor 2, Nrf2）是一种含有亮氨酸拉链基本结构的转录因子，属于Cap-n-collar（CNC）调节蛋白家族，是机体抵抗内外界氧化和化学等刺激的重要的防御性转导通路，促进细胞内氧化还原环境的调节。