title: Cilostazol attenuates murine hepatic ischemia and reperfusion injury via heme oxygenase-dependent activation of mitochondrial biogenesis.
abstract: Hepatic ischemia-reperfusion (I/R) can cause hepatocellular injury associated with the inflammatory response and mitochondrial dysfunction. We studied the protective effects of the phosphodiesterase inhibitor cilostazol in hepatic I/R and the roles of mitochondria and the Nrf2/heme oxygenase-1 (HO-1) system. Wild-type, Hmox1(-/-), or Nrf2(-/-) mice were subjected to hepatic I/R in the absence or presence of cilostazol followed by measurements of liver injury. Primary hepatocytes were subjected to cilostazol with the HO-1 inhibitor ZnPP, or Nrf2-specific siRNA, followed by assessment of mitochondrial biogenesis. Preconditioning with cilostazol prior to hepatic I/R protected against hepatocellular injury and mitochondrial dysfunction. Cilostazol reduced the serum levels of alanine aminotransferase, TNF-α, and liver myeloperoxidase content relative to control I/R-treated mice. In primary hepatocytes, cilostazol increased the expression of HO-1, and markers of mitochondrial biogenesis, PGC-1α, NRF-1, and TFAM, induced the mitochondrial proteins COX III and COX IV and increased mtDNA and mitochondria content. Pretreatment of primary hepatocytes with ZnPP inhibited cilostazol-induced PGC-1α, NRF-1, and TFAM mRNA expression and reduced mtDNA and mitochondria content. Genetic silencing of Nrf2 prevented the induction of HO-1 and mitochondrial biogenesis by cilostazol in HepG2 cells. Cilostazol induced hepatic HO-1 production and mitochondrial biogenesis in wild-type mice, but not in Hmox1(-/-) or Nrf2(-/-) mice, and failed to protect against liver injury in Nrf2(-/-) mice. These results suggest that I/R injury can impair hepatic mitochondrial function, which can be reversed by cilostazol treatment. These results also suggest that cilostazol-induced mitochondrial biogenesis was mediated by an Nrf-2- and HO-1-dependent pathway.
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan, Korea;
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan, Korea; Department of Neurology, Affiliated Hospital of YanBian University, YanJi, China;
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan, Korea;
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan, Korea;
authors.forename: Md Jamal
authors.initials: MJ
authors.lastname: Uddin
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan, Korea;
authors.forename: Seul-Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan, Korea;
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan, Korea;
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Anatomy, School of Medicine, and Institute of Health Sciences, Gyeongsang National University, Jinju, Korea; and.
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, and Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical Center, New York, New York.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan, Korea; chung@ulsan.ac.kr.
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
mesh_terms: D000818:Animals; D000077407:Cilostazol; D019610:Cytoprotection; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D063269:Mitochondrial Turnover / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058987:Phosphodiesterase 3 Inhibitors; C485290:Ppargc1a protein, mouse; D020011:Protective Agents; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013777:Tetrazoles; C081930:Tfam protein, mouse; D014157:Transcription Factors; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000077407:Cilostazol
keywords: HO-1; Nrf-2; cilostazol; ischemia-reperfusion; mitochondrial biogenesis