Details

Autor(en) / Beteiligte

• Zhou, Shanshan
• Yin, Xia
• Jin, Jingpeng
• Tan, Yi
• Conklin, Daniel J.
• Xin, Ying
• Zhang, Zhiguo
• Sun, Weixia
• Cui, Taixing
• Cai, Jun
• Zheng, Yang
• Cai, Lu

Titel

Intermittent hypoxia-induced cardiomyopathy and its prevention by Nrf2 and metallothionein

Ist Teil von

• Free radical biology & medicine, 2017-11, Vol.112, p.224-239

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• The mechanism for intermittent hypoxia (IH)-induced cardiomyopathy remains obscure. We reported the prevention of acute and chronic IH-induced cardiac damage by selective cardiac overexpression of metallothionein (MT). Herein we defined that MT-mediated protection from IH-cardiomyopathy is via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a critical redox-balance controller in the body. For this, mice were exposed to IH for 3 days (acute) or 4 or 8 weeks (chronic). Cardiac Nrf2 and MT expression in response to IH were significantly increased acutely yet decreased chronically. Interestingly, cardiac overexpression (Nrf2-TG) or global deletion of the Nrf2 gene (Nrf2-KO) made mice highly resistant or highly susceptible, respectively, to IH-induced cardiomyopathy and MT expression. Mechanistically, 4-week IH exposure significantly decreased cardiac Nrf2 binding to the MT gene promoter, and thus, depressed both MT transcription and translation in WT mice but not Nrf2-TG mice. Likewise, cardiac MT overexpression prevented chronic IH-induced cardiomyopathy and down-regulation of Nrf2 likely via activation of a PI3K/Akt/GSK-3β/Fyn-dependent signaling pathway. These results reveal an integrated relationship between cardiac Nrf2 and MT expression in response to IH -- acute compensatory up-regulation followed by chronic down-regulation and cardiomyopathy. Cardiac overexpression of either Nrf2 or MT offered cardioprotection from IH via complicated PI3K/Akt/GSK3B/Fyn signaling. Potential therapeutics may target either Nrf2 or MT to prevent chronic IH-induced cardiomyopathy. [Display omitted] •Cardiac Nrf2 and MT expressions respond in parallel to intermittent hypoxia (IH).•Both expression are decreased at late stage with the development of cardiomyopathy.•Nrf2 plays a key role in preventing IH-induced cardiac oxidative stress and damage.•Cardiac Nrf2 and MT expressions are under beneficial feedback control.•MT positively affects Nrf2 function via PI3K/Akt/GSK-3β/Fyn signaling pathway.