Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 277, Issue 1, Pages 58-66Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2014.03.007
Keywords
Obstructive sleep apnea; Intermittent hypoxia; Metallothionein; Cardiomyopathy; Oxidative damage
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Funding
- American Diabetes Association [1-11-BS-17]
- Sleep Research Society Foundation/J. Christian Gillin M.D. [001GN09]
- Wenzhou Medical College
- Natural Science Foundation of China (NSFC) [81273509, 81200239]
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Obstructive sleep apnea (USA) causes chronic intermittent hypoxia (1H) to induce cardiovascular disease, which may be related to oxidative damage. Metallothionein (MT) has been extensively proved to be an endogenous and highly inducible antioxidant protein expressed in the heart. Therefore, we tested the hypotheses that oxidative stress plays a critical role in USA induced cardiac damage and MT protects the heart from OSA-induced cardiomyopathy. To mimic hypoxia/reoxygenation events that occur in adult USA patients, mice were exposed to IH for 3 days to 8 weeks. The IH paradigm consisted of alternating cycles of 20.9% O-2/8% O-2 F1O2 (30 episodes per hour) with 20s at the nadir F1O2 for 12 ha day during daylight IH significantly increased the ratio of heart weight to tibia length at 4 weeks with a decrease in cardiac function from 4 to 8 weeks. Cardiac oxidative damage and fibrosis were observed after 4 and 8 weeks of IH exposures. Endogenous MT expression was up-regulated in response to 3-day IH, but significantly decreased at 4 and 8 weeks of IH. In support of MT as a major compensatory component, mice with cardiac overexpression of MT gene and mice with global MT gene deletion were completely resistant, and highly sensitive, respectively, to chronic IH induced cardiac effects. These findings suggest that chronic 1H induces cardiomyopathy characterized by oxidative stress-mediated cardiac damage and the antioxidant MT protects the heart from such pathological and functional changes. (C) 2014 Elsevier Inc. All rights reserved.
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