Seul-Ki Kim

University of Ulsan, Urusan, Ulsan, South Korea

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Publications (8)32.83 Total impact

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    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. HepG2 cells 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 ALT, TNF-α and liver myeloperoxidase content relative to control I/R-treated mice. In cultured HepG2 cells, 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. Pre-treatment of HepG2 cells 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.
    AJP Gastrointestinal and Liver Physiology 05/2015; DOI:10.1152/ajpgi.00307.2014 · 3.74 Impact Factor
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    ABSTRACT: The immunoresponsive gene 1 (IRG1) protein has crucial functions in embryonic implantation and neurodegeneration. IRG1 promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species (ROS). The cytoprotective protein heme oxygenase-1 (HO-1), which generates endogenous carbon monoxide (CO), is expressed in the lung during Lipopolysaccharide (LPS) tolerance and cross tolerance. However, the detailed molecular mechanisms and functional links between IRG1 and HO-1 in the innate immune system remain unknown. In the present study, we found that the CO releasing molecule-2 (CORM-2) and chemical inducers of HO-1 increased IRG1 expression in a time- and dose-dependent fashion in RAW264.7 cells. Furthermore, inhibition of HO-1 activity by zinc protoporphyrin IX (ZnPP) and HO-1 siRNA significantly reduced expression of IRG1 under these conditions. In addition, treatment with CO and HO-1 induction significantly increased A20 expression, which was reversed by ZnPP and HO-1 siRNA. LPS-stimulated TNF-α was significantly decreased, whereas IRG1 and A20 were increased by CORM-2 application and HO-1 induction, which in turn were abrogated by ZnPP. Interestingly, siRNA against IRG1 and A20 reversed the effects of CO and HO-1 on LPS-stimulated TNF-α production. Additionally, CO and HO-1 inducers significantly increased IRG1 and A20 expression and downregulated TNF-α production in a LPS-stimulated sepsis mice model. Furthermore, the effects of CO and HO-1 on TNF-α production were significantly reversed when ZnPP was administered. In conclusion, CO and HO-1 induction regulates IRG1 and A20 expression, leading to inhibition of inflammation in vitro and in an in vivo mice model.
    Cellular & molecular immunology 02/2015; DOI:10.1038/cmi.2015.02. · 4.19 Impact Factor
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    ABSTRACT: The regeneration of mitochondria by regulated biogenesis plays an important homeostatic role in cells and tissues and furthermore may provide an adaptive mechanism in certain diseases such as sepsis. The heme oxygenase (HO-1)/carbon monoxide (CO) system is an inducible cytoprotective mechanism in mammalian cells. Natural antioxidants can provide therapeutic benefit, in part, by inducing the HO-1/CO system. This study focused on the mechanism by which the natural antioxidant quercetin can induce mitochondrial biogenesis in HepG2 cells. We found that quercetin treatment induced expression of mitochondrial biogenesis activators (PGC-1 α , NRF-1, TFAM), mitochondrial DNA (mtDNA), and proteins (COX IV) in HepG2 cells. The HO inhibitor SnPP and the CO scavenger hemoglobin reversed the effects of quercetin on mitochondrial biogenesis in HepG2 cells. The stimulatory effects of quercetin on mitochondrial biogenesis could be recapitulated in vivo in liver tissue and antagonized by SnPP. Finally, quercetin conferred an anti-inflammatory effect in the liver of mice treated with LPS and prevented impairment of mitochondrial biogenesis by LPS in vivo. These salutary effects of quercetin in vivo were also antagonized by SnPP. Thus, our results suggest that quercetin enhances mitochondrial biogenesis mainly via the HO-1/CO system in vitro and in vivo. The beneficial effects of quercetin may provide a therapeutic basis in inflammatory diseases and sepsis.
    Oxidative Medicine and Cellular Longevity 10/2013; 2013:154279. DOI:10.1155/2013/154279 · 3.36 Impact Factor
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    ABSTRACT: Aims: Nitric oxide (NO) can induce mitochondrial biogenesis in cultured cells, through increased cGMP, and activation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We sought to determine the role of NO, heme oxygenase-1, and its reaction product (CO) in the induction of mitochondrial biogenesis by the natural antioxidant resveratrol. Results: S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced mitochondrial biogenesis in HepG2 hepatoma cells, and in vivo, through stimulation of PGC-1α. NO-induced mitochondrial biogenesis required cGMP, and was mimicked by the cGMP analogue (8-Br-cGMP). Activation of mitochondrial biogenesis by SNAP required heme oxygenase-1 (HO-1), as it could be reversed by genetic interference of HO-1; and by treatment with the HO inhibitor tin-protoporphyrin-IX (SnPP) in vitro and in vivo. Cobalt protoporphyrin-IX (CoPP), a HO-1 inducing agent, stimulated mitochondrial biogenesis in HepG2 cells, which could be reversed by the CO scavenger hemoglobin. Application of CO, using the CO-releasing molecule (CORM-3) stimulated mitochondrial biogenesis in HepG2 cells, in a cGMP-dependent manner. Both CoPP and CORM-3-induced mitochondrial biogenesis required NF-E2-related factor-2 (Nrf2) activation, and phosphorylation of Akt. The natural antioxidant resveratrol induced mitochondrial biogenesis in HepG2 cells, in a manner dependent on NO biosynthesis, cGMP synthesis, Nrf-2-dependent HO-1 activation, and endogenous CO production. Furthermore, resveratrol preserved mitochondrial biogenesis during LPS-induced hepatic inflammation in vivo. Innovation and Conclusions: The complex interplay between endogenous NO and CO production may underlie the mechanism by which natural antioxidants induce mitochondrial biogenesis. Strategies aimed at improving mitochondrial biogenesis may be used as therapeutics for the treatment of diseases involving mitochondrial dysfunction.
    Antioxidants & Redox Signaling 09/2013; DOI:10.1089/ars.2012.5138 · 7.67 Impact Factor
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    ABSTRACT: Leptin, a circulating hormone, regulates food intake and body weight. While leptin resistance represents a major cause of obesity, the underlying mechanisms remain unclear. Endoplasmic reticulum (ER) stress can contribute to leptin resistance. Carbon monoxide (CO), a gaseous molecule, exerts anti-apoptotic and anti-inflammatory effects in animal models of tissue injury. We hypothesized that CO can inhibit leptin resistance during ER stress. Thapsigargin or tunicamycin were used to induce ER stress in human cells expressing the leptin receptor. These agents markedly inhibited leptin-induced STAT3 phosphorylation, confirming that ER stress induces leptin resistance. The CO-releasing molecule (CORM-2) blocked the ER stress-dependent inhibition of leptin-induced STAT3 phosphorylation. CORM-2-treatment induced the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK), and eukaryotic translation initiation factor-2α and enhanced PERK phosphorylation during ER stress. Furthermore, CORM-2 inhibited X-box binding protein-1 expression, ATF-6 cleavage, and IRE1α phosphorylation induced by ER stress. IRE1α knockdown rescued leptin resistance, whereas PERK knockdown blocked CO-dependent regulation of IRE1α. In vivo, CO inhalation normalized body weight in animals fed high fat diets. Furthermore, CO modulated ER stress pathways and rescued leptin resistance in vivo. In conclusion, the pathological mechanism of leptin resistance may be ameliorated by the pharmacological application of CO.
    AJP Endocrinology and Metabolism 02/2013; 304(7). DOI:10.1152/ajpendo.00466.2012 · 4.09 Impact Factor
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    ABSTRACT: Endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response, allowing cells to recover folding capacity in the organelle. However, the overwhelming response to severe damage results in apoptotic cell death. Because of the physical proximity between ER and mitochondria, a functional interrelationship between these two organelles, including mitochondrial ATP production and apoptosis, has been suggested. The adaptive response to ER stress includes the maintenance of cellular energetics, which eventually determines cell fate. We previously demonstrated that heme oxygenase-1 (HO-1) activity protects cells against ER stress in a protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent pathway. Here, we provide evidence that PERK-mediated induction of HO-1 in murine macrophages, RAW264.7, relays ER stress to mitochondrial DNA (mtDNA) replication and function. ER stress induced by thapsigargin treatments (10-100 nM) resulted in a 2-fold increase in mtDNA contents compared with that in the untreated control. HO-1 activity on ER stress is proven to be critical for mitochondrial integrity because chemical inhibition (zinc protoporphyrin, 5-20 μM) and genetic depletion of HO-1 by small interference RNA transfection suppress the activation of transcription factors for mitochondrial biogenesis. Carbon monoxide (CO), an enzymatic by-product of HO-1 activity is responsible for the function of HO-1. Limited bioavailability of CO by hemoglobin treatment triggers cell death with a concomitant decline in ATP production. Approximately 78.1% of RAW264.7 cells were damaged in the presence of hemoglobin compared with the percentage of injured cells (26.9%) under ER stress alone. Mitochondrial generation of ATP levels significantly declined when CO availability was limited under prolonged ER stress. Taken together, these results suggest that the cellular HO-1/CO system conveys ER stress to cell survival signals from mitochondria via both the activation of transcriptional factors and functional integrity of mtDNA.
    The FASEB Journal 03/2012; 26(6):2558-68. DOI:10.1096/fj.11-199604 · 5.48 Impact Factor
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    ABSTRACT: Carbon monoxide (CO) is a cytoprotective and homeostatic molecule with important signaling capabilities in physiological and pathophysiological situations. CO protects cells/tissues from damage by free radicals or oxidative stress. NAD(P)H:quinone oxidoreductase (NQO1) is a highly inducible enzyme that is regulated by the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, which is central to efficient detoxification of reactive metabolites and reactive oxygen species (ROS). We generated NQO1 promoter construct. HepG2 cells were treated with CO Releasing Molecules-2 (CORM-2) or CO gas and the gene expressions were measured by RT-PCR, immunoblot, and luciferase assays. CO induced expression of NQO1 in human hepatocarcinoma cell lines by activation of Nrf2. Exposure of HepG2 cells to CO resulted in significant induction of NQO1 in dose- and time-dependent manners. Analysis of the NQO1 promoter indicated that an antioxidant responsible element (ARE)-containing region was critical for the CO-induced Nrf2-dependent increase of NQO1 gene expression in HepG2 cells. Our results suggest that CO-induced Nrf2 increases the expression of NQO1 which is well known to detoxify reactive metabolites and ROS.
    Immune Network 12/2011; 11(6):376-82. DOI:10.4110/in.2011.11.6.376
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    ABSTRACT: Metabolic disease is a complex disorder defined by various factors that increase the risk of cardiovascular disease and type 2 diabetes mellitus. In recent years, the incidence of chronic metabolic disease has dramatically increased throughout the world. These chronic metabolic diseases are associated with elevated inflammatory activities. In addition, endoplasmic reticulum (ER) stress leads to metabolic syndrome. Inflammation and ER stress are linked in the context of metabolic homeostasis and disease. Carbon monoxide (CO), a reaction product of heme oxygenase-1 (HO-1), reduces oxidative stress and inflammatory response and protects cells from ER stress. CO has anti-inflammatory effects via induction of HO-1 expression and prevents ER stress-induced apoptosis by inhibiting the C/EBP homologous protein expression. In addition to its anti-inflammatory effects and antiapoptotic effects, HO-1 plays an important role in insulin release and glucose metabolism. In our study, inhalation of CO gas or CO-releasing molecule injection ameliorates 30% fructose or methionine-deficient- and choline-deficient-diet-induced hepatic steatosis. Therefore, CO can be studied in the search for potential therapeutic targets for metabolic diseases via inhibition of inflammatory response and ER stress.
    Annals of the New York Academy of Sciences 07/2011; 1229(1):156-61. DOI:10.1111/j.1749-6632.2011.06121.x · 4.31 Impact Factor