Abstract 79: Nrf2 Protects From Intermittent Hypoxia-induced Cardiomyopathy via Metallothionein-dependent and Independent Mechanisms

• DOI: 10.1161/res.117.suppl_1.79
• Publication Date: 2021-07-03T12:00:32Z
• Authors: Shanshan Zhou; Xia Yin; Jingpeng Jin; Ying Xin; Yi Tan; Zhiguo Zhang; Weixia Sun; Taixing Cui; Jun Cai; Yang Zheng; Lu Cai
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

Background: We recently reported that cardiac expression of the antioxidant metallothionein (MT) was increased by acute expsorue to intermittent hypoxia (IH), and protected from chronic IH-induced cardiomyopathy. However, how IH stimulates MT in the heart remains unclear. Here we tried to define whether nuclear factor erythroid 2-related factor 2 (Nrf2), a critical redox-balance controller in the body, protects from IH-induced cardiomyopathy and its relationship with MT, and whether Nrf2 and MT are indispensable for sulforaphane (SFN) prevention of IH-induced cardiomyopathy.

Methods and Results: Mice were exposed to IH for 3 days to 8 weeks. Like MT, cardiac Nrf2 expression was significantly increased in response to 3-day IH, but decreased in response to 4- or 8-week IH. Mice with cardiac overexpression or global deletion of the Nrf2 gene (Nrf2-TG or Nrf2-KO) were completely resistant or susceptible to IH-induced cardiomyopathy. Cardiac protection from IH by endogenous Nrf2 and MT are indispensable each other. Mechanistically 4-week exposure to IH significantly decreased cardiac Nrf2 binding to the promoter of MT, lowing its transcription and translation. MT stimulated Nrf2 function via activation of PI3K/Akt/GSK-3β/Fyn signaling pathway in a feedback manner. Furthermore, Nrf2 inducer SFN prevented IH-induced cardiomyopathy in both WT and MT-KO mice, but not Nrf2-KO mice.

Conclusions: These results suggest that a reciprocal regulation between Nrf2 and MT is necessary for an efficiently antioxidant response to and protection from IH. However, the protective effect of SFN on IH-induced cardiomyopathy is Nrf2-dependent, instead of MT.