Higenamine regulates Nrf2-HO-1-Hmgb1 axis and attenuates intestinal ischemia-reperfusion injury in mice

Intestinal ischemia and reperfusion (IR) syndrome is a life-threatening dilemma caused by diverse events. Higenamine (HG), an active ingredient of Aconiti Lateralis Radix Praeparata, has been traditionally used as a heart stimulant and anti-inflammatory agent in oriental countries. But the function of HG on intestine IR injury has never been investigated. Mice underwent a 2 cm midline laparotomy, and the superior mesenteric artery (SMA) was obstructed by micro-vascular clamp to induce intestinal ischemia. In our current study, HG increases mouse intestinal epithelial (IEC-6) cell viability through induced heme oxygenase-1 (HO-1) production in vitro. In our in vivo murine intestinal IR injury model, the increased HO-1 protein level and activity, decreased intestinal injury score, Myeloperoxidase (MPO) activity, and inflammatory cytokine expression induced by HG were all abolished with additional treatment of HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX). Furthermore, HG reduced high mobility group box-1 (Hmgb1) expression in IR injury-performed intestine which was inhibited by additional administration of ZnPPIX. And HG treatment significantly decreased HO-1 expression in nuclear factor erythroid 2-related factor (Nrf-2) SiRNA-transfected cells but not in control SiRNA-transfected cells. Our study provides evidence HG regulates Nrf2-HO-1-Hmgb1 axis and attenuates intestinal IR injury in mice.