d-Chiro inositol ameliorates endothelial dysfunction via inhibition of oxidative stress and mitochondrial fission

Abstract

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.

Keywords: AMPK; Endothelial dysfunction; Mitochondrial fission; NOX4 oxidase; d-chiro inositol.