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Blockade of PKCβ protects against remote organ injury induced by intestinal ischemia and reperfusion via a p66shc-mediated mitochondrial apoptotic pathway

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Abstract

Intestinal ischemia–reperfusion (I/R) is a serious clinical dilemma with high morbidity and mortality. Remote organ damage, especially acute lung injury and liver injury are common complications that contribute to the high mortality rate. We previously demonstrated that activation of PKCβII is specifically involved in the primary injury of intestinal I/R. Considering the tissue-specific features of PKC activation, we hypothesized that some kind of PKC isoform may play important roles in the progression of secondary injury in the remote organ. Mice were studied in in vivo model of intestinal I/R. The activation of PKC isoforms were screened in the lung and liver. Interestingly, we found that PKCβII was also activated exclusively in the lung and liver after intestinal I/R. PKCβII suppression by a specific inhibitor, LY333531, significantly attenuated I/R-induced histologic damage, inflammatory cell infiltration, oxidative stress, and apoptosis in these organs, and also alleviated systemic inflammation. In addition, LY333531 markedly restrained p66shc activation, mitochondrial translocation, and binding to cytochrome-c. These resulted in the decrease of cytochrome-c release and caspase-3 cleavage, and an increase in glutathione and glutathione peroxidase. These data indicated that activated PKC isoform in the remote organ, specifically PKCβII, is the same as that in the intestine after intestinal I/R. PKCβII suppression protects against remote organ injury, which may be partially attributed to the p66shc-cytochrome-c axis. Combined with our previous study, the development of a specific inhibitor for prophylaxis against intestinal I/R is promising, to prevent multiple organ injury.

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Acknowledgments

This work was supported by grants from the Chinese National Natural Science Foundation (No. 81171850, 81372037).

Conflict of interests

The authors have no competing interests to declare.

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Authors and Affiliations

  1. Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, 116023, China

    Guangzhi Wang, Zhao Chen, Feng Zhang, Huirong Jing, Wei Xu, Shili Ning, Zhenlu Li & Xiaofeng Tian

  2. Department of Pharmacology, Dalian Medical University, Dalian, 116044, China

    Kexin Liu & Jihong Yao

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  1. Guangzhi Wang
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Correspondence to Jihong Yao or Xiaofeng Tian.

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Wang, G., Chen, Z., Zhang, F. et al. Blockade of PKCβ protects against remote organ injury induced by intestinal ischemia and reperfusion via a p66shc-mediated mitochondrial apoptotic pathway. Apoptosis 19, 1342–1353 (2014). https://doi.org/10.1007/s10495-014-1008-x

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