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p53-independent Induction of PUMA Mediates Intestinal Apoptosis in Response to Ischemia Reperfusion
  1. Bin Wu
  1. Unversity of Pittsburgh, United States
    1. Wei Qiu
    1. Unversity of Pittsburgh, United States
      1. Peng Wang
      1. Unversity of Pittsburgh, United States
        1. Hiu Yu
        1. Unversity of Pittsburgh, United States
          1. Tao Cheng
          1. Unversity of Pittsburgh, United States
            1. Gerard P Zambetti
            1. St. Jude Children's Research Hospital, United States
              1. Lin Zhang
              1. Unversity of Pittsburgh, United States
                1. Jian Yu (yuj2{at}upmc.edu)
                1. Unversity of Pittsburgh, United States

                  Abstract

                  Background: The small intestine is highly sensitive to ischemia reperfusion (I/R)-induced injury, which is associated with high morbidity and mortality. Apoptosis, or programmed cell death, is a major mode of cell death occurring during I/R-induced injury. However, the mechanisms by which I/R cause apoptosis in small intestine are poorly understood. PUMA is a p53 downstream target and a member of BH3-only group of Bcl-2 family proteins. It has been shown that PUMA plays an essential role in apoptosis induced by a variety of stimuli in different tissues through a mitochondrial pathway.

                  Aims: In this study, we investigated the role of PUMA in I/R-induced injury and apoptosis in small intestine. We also studied the mechanisms by which PUMA is regulated in I/R-induced intestinal apoptosis.

                  Methods: Ischemia was induced by superior mesenteric artery occlusion in mouse small intestine. Induction of PUMA in response to ischemia alone, or ischemia followed by reperfusion (I/R) was examined. I/R-induced intestinal apoptosis and injury were compared between PUMA knockout and wild-type mice. The mechanisms of I/R-induced and PUMA-mediated apoptosis were investigated through analysis of caspase activation, cytosolic release of mitochondrial cytochrome c, and alterations of the proapoptotic Bcl-2 family proteins Bax and Bak. To determine whether PUMA is induced by reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) generated by I/R, superoxide dismutase (SOD) and N-nitro-L-arginine methyl ester (L-NAME) were used to treat animals before I/R. To determine whether p53 is involved in regulating PUMA during I/R-induced apoptosis, PUMA induction and apoptosis in response to I/R were examined in p53 knockout mice.

                  Results: PUMA was markedly induced following ischemia reperfusion in the mucosa of the mouse small intestine. I/R-induced intestinal apoptosis was significantly attenuated in the PUMA knockout mice compared with that in the wild-type mice. I/R-induced caspase 3 activation, cytochrome c release, Bax mitochondrial translocation, and Bak multimerzation were also inhibited in the PUMA knockout mice. SOD or L-NAME significantly blunted I/R-induced PUMA expression and apoptosis. Furthermore, I/R-induced PUMA expression and apoptosis in small intestine were not affected in the p53 knockout mice.

                  Conclusions: Our data demonstrated that PUMA is activated by oxidative stress in response to I/R to promote p53-independent apoptosis in small intestine through the mitochondrial pathway. Inhibition of PUMA is potentially useful for protecting against I/R-induced intestinal injury and apoptosis.

                  • PUMA
                  • apoptosis
                  • ischemia reperfusion
                  • oxidative stress
                  • small intestine

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