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Apoptosis is a major mode of cell death occurring during ischemia–reperfusion (I/R) induced injury. The p66 Shc  adaptor protein, which is mediated by PKC β , has an essential role in apoptosis under oxidative stress. This study aimed to investigate the role of PKC β  2 /p66 Shc  pathway in intestinal I/R injury.  In vivo , ischemia was induced by superior mesenteric artery occlusion in mice. Ruboxistaurin (PKC β  inhibitor) or normal saline was administered before ischemia. Then blood and gut tissues were collected after reperfusion for various measurements.  In vitro , Caco-2 cells were challenged with hypoxia–reoxygenation (H/R) to simulate intestinal I/R. Translocation and activation of PKC β  2  were markedly induced in the I/R intestine. Ruboxistaurin significantly attenuated gut damage and decreased the serum levels of tumor necrosis factor- α  (TNF- α ) and interleukin-6 (IL-6). Pharmacological blockade of PKC β  2  suppressed p66 Shc  overexpression and phosphorylation in the I/R intestine. Gene knockdown of PKC β  2  via small interfering RNA (siRNA) inhibited H/R-induced p66 Shc  overexpression and phosphorylation in Caco-2 cells. Phorbol 12-myristate 13-acetate (PMA), which stimulates PKCs, induced p66 Shc  phosphorylation and this was inhibited by ruboxistaurin and PKC β  2  siRNA. Ruboxistaurin attenuated gut oxidative stress after I/R by suppressing the decreased expression of manganese superoxide dismutase (MnSOD), the exhaustion of the glutathione (GSH) system, and the overproduction of malondialdehyde (MDA). As a consequence, ruboxistaurin inhibited intestinal mucosa apoptosis after I/R. Therefore, PKC β  2  inhibition protects mice from gut I/R injury by suppressing the adaptor p66 Shc -mediated oxidative stress and subsequent apoptosis. This may represent a novel therapeutic approach for the prevention of intestinal I/R injury.

Selective inhibition of protein kinase C β2 attenuates the adaptor P66Shc-mediated intestinal ischemia–reperfusion injury