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d ‐Chiro inositol ameliorates endothelial dysfunction via inhibition of oxidative stress and mitochondrial fission
Author(s) -
Zhang Bobo,
Guo Xudan,
Li Yunlong,
Peng Qiang,
Gao Jinfeng,
Liu Baolin,
Wang Min
Publication year - 2017
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201600710
Subject(s) - nox4 , mitochondrial fission , oxidative stress , ampk , chemistry , oxidative phosphorylation , endothelial dysfunction , mitochondrion , microbiology and biotechnology , phosphorylation , biology , endocrinology , nadph oxidase , biochemistry , protein kinase a
Scope d ‐chiro inositol (DCI), an isomer of inositol, possesses anti‐oxidative and endothelial protective properties. The mechanism by which DCI prevents endothelial dysfunction was investigated, with emphasis on oxidative stress. Methods and results DCI was found to inhibit NOX4 induction and enhance Nrf2 activity in palmitate (PA)‐stimulated cells, showing that DCI prevents oxidative stress. DCI suppressed Ser616 phosphorylation and increased Ser637 phosphorylation of Drp1 and inhibited PA‐induced mitochondrial fission. Knockdown of Drp1 attenuated NOX4 over‐expression and increased the inhibitory effect of DCI. In addition, DCI enhanced AMPK activity through the LKB1‐dependent pathway. AMPK knockdown diminished the inhibitory effect of DCI on Drp1/NOX4 induction, indicating that AMPK is essential for Drp1 and NOX4 suppression by DCI. As a result, DCI inhibited cell apoptosis against PA insults. Consistent with the effects observed in cells, DCI reversed endothelial dysfunction in rat aorta rings under lipid‐challenged conditions. In high fat‐fed mice, oral administration of DCI inhibited Drp1/NOX4 induction and enhanced NO generation in the aortic endothelium, confirming its protective role in endothelial function in vivo. Conclusion Drp1 activation‐induced mitochondrial fission and NOX4 over‐expression are associated with endothelial injury. DCI prevented endothelial dysfunction by inhibiting oxidative stress and mitochondrial fission in an AMPK‐dependent manner.