Abstract
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. 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. 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.
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