Blockade of PKCβ protects against remote organ injury induced by intestinal ischemia and reperfusion via a p66shc-mediated mitochondrial apoptotic pathway
Autor: | Huirong Jing, Shili Ning, Zhenlu Li, Feng Zhang, Jihong Yao, Xiaofeng Tian, Kexin Liu, Guangzhi Wang, Zhao Chen, Wei Xu |
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Rok vydání: | 2014 |
Předmět: |
Male
Cancer Research Indoles Src Homology 2 Domain-Containing Transforming Protein 1 Clinical Biochemistry Pharmaceutical Science Apoptosis Biology Lung injury Pharmacology Systemic inflammation medicine.disease_cause Protective Agents Maleimides chemistry.chemical_compound In vivo Protein Kinase C beta medicine Animals Lung Protein Kinase Inhibitors Liver injury chemistry.chemical_classification Mice Inbred ICR Caspase 3 Glutathione peroxidase Biochemistry (medical) Cytochromes c Cell Biology Glutathione medicine.disease Mitochondria Intestines chemistry Liver Shc Signaling Adaptor Proteins Reperfusion Injury Immunology medicine.symptom Oxidative stress Signal Transduction |
Zdroj: | Apoptosis : an international journal on programmed cell death. 19(9) |
ISSN: | 1573-675X |
Popis: | 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. |
Databáze: | OpenAIRE |
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