Prevention Of Intermittent Hypoxia-induced Cardiomyopathy By Reciprocal Stimulation Between Nuclear Factor Erythroid2-related Factor2and Metallothionein

Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (IH) toinduce cardiovascular disease, which may be related to oxidative damage. Inour previous study, we also demonstrated chronic IH induces cardiomyopathycharacterized by cardiac oxidative stress damage and dysfunction, and theantioxidant MT protects the heart from such pathological and functionalchanges. Nuclear factor erythroid2-related factor2(Nrf2) is a mastertranscription factor that plays a critical role in the regulation of antioxidantdefense genes.Aim: This study was to investigate the role of nuclear factor erythroid2-related factor2(Nrf2), as an critical control for redox balance in the body, inIH-induced cardiac injury and its relationship with MT, and also to determinewhether Nrf2or MT is indispensable to sulforaphane (SFN) prevention ofcardiac injury in response to IH.Method: To mimic hypoxia/reoxygenation events that occur in adult OSApatients, mice were exposed to IH for3days to8weeks. Briefly, adult micewere exposed to an IH profile designed to produce similar nadir hemoglobinoxygen saturations (60~70%) as observed in moderate to severe OSA patients.The IH paradigm consisted alteration cycles of20.9%O2/8%O2FiO2(30episodes per hour) with20seconds at the nadir FiO2during the12-hr light phase.Result: Cardiac Nrf2and MT expression were both increased in response to3-day IH, but significantly decreased at4and8weeks of IH. In support ofNrf2as a major compensatory component, mice with cardiac overexpressionof the Nrf2gene or with global deletion of the Nrf2gene were completelyresistant or highly sensitive, respectively, to chronic IH-induced cardiac effects.Mechanistic study showed that in response to IH for3days, cardiac Nrf2bindswith the promoter of MT to promote its expression, and in feedback MTstimulates Nrf2function via activation of PI3K/Akt/GSK-3β/Fyn signalingpathway. To further confirm the indispensable role of Nrf2for preventingIH-induced cardiac damage, Nrf2inducer SFN was found to preventIH-induced cardiac oxidative damage and dysfunction in both WT and MT-KOmice, but not Nrf2-KO mice.Conclusion: These results suggest the reciprocal regulation between Nrf2andMT is necessary for an efficient protection against IH-induced cardiac injury.However, the protective effect of SFN is mediated by the Nrf2signalingpathway, instead of MT.