Nrf2 expression and function, but not MT expression, is indispensable for sulforaphane-mediated protection against intermittent hypoxia-induced cardiomyopathy in mice

• Main Authors: Shanshan Zhou, Jiqun Wang, Xia Yin, Ying Xin, Zhiguo Zhang, Taixing Cui, Jun Cai, Yang Zheng, Quan Liu, Lu Cai
• Format: Article
• Language: English
• Published: Elsevier 2018-10-01
• Series: Redox Biology
• Online Access: http://www.sciencedirect.com/science/article/pii/S221323171830466X

We reported previously that nuclear factor erythroid 2-related factor 2 (Nrf2) and metallothionein (MT) play critical roles in preventing intermittent hypoxia (IH)-induced cardiomyopathy. In addition, positive feedback regulation between Nrf2 and MT is required for the efficient compensative responses of the heart to IH. As an activator of Nrf2, sulforaphane (SFN) has attracted attention as a potential protective agent against cardiovascular disease. Here, we investigated whether SFN can up-regulate cardiac Nrf2 expression and function, as well as MT expression, to prevent IH-induced cardiomyopathy, and if so, whether Nrf2 and MT are indispensable for this preventive effect. Nrf2-knock-out (Nrf2-KO) or MT-KO mice and their wild-type (WT) equivalents were exposed to IH for 4 weeks with or without SFN treatment. SFN almost completely prevented IH-induced cardiomyopathy in WT mice, and this preventive effect was abolished in Nrf2-KO mice but retained in MT-KO mice. In IH-exposed WT mice, SFN induced significant increases in the expression levels of Nrf2 and its downstream antioxidant target genes, as well as those of MT, but these effects were not seen in IH-exposed Nrf2-KO mice. By contrast, KO of MT did not affect the ability of SFN to up-regulate the expression of Nrf2 and its downstream antioxidant targets. These results suggest that SFN-induced MT expression is Nrf2-dependent, and SFN prevents IH-induced cardiomyopathy in a Nrf2-dependent manner, for which MT is dispensable. This study provides important information that is relevant to the potential use of SFN to prevent IH-induced cardiomyopathy. Keywords: Intermittent hypoxia, Cardiomyopathy, Nuclear factor erythroid 2-related factor 2, Metallothionein, Sulforaphane