11:10-12:00, Rm 103

Cardiovascular Diseaseoxidant, reduces the critical cysteine residues in cII-HDACs, thereby restoring the nuclearlocalization of cII-HDACs and inhibiting pathological hypertrophy, suggesting that OPTMof cII-HDACs can be a therapeutic target of cardiac hypertrophy and heart failure. Then,where and how is oxidative stress generated during cardiac hypertrophy? It has beenshown that leakage of electrons from mitochondria is a major source of oxidative stressduring cardiac hypertrophy and heart failure. However, recent evidence suggests thatother sources may also contribute to oxidative stress. The NADPH oxidase family is agroup of membrane-associated proteins producing superoxide and hydrogen peroxide.Nox4, one of the major isoforms in the heart, is localized on intracellular membranes,including those in mitochondria, endoplasmic reticulum and nucleus. Using cardiacspecific Nox4 KO mice, we have shown recently that Nox4 is a major source ofsuperoxide production in mitochondria and that upregulation of Nox4 mediatesmitochondrial dysfunction and cardiac dysfunction in response to pressure overload.Nox4 is also localized on the nuclear membrane and mediates oxidation of cII-HDACs inresponse to hypertrophic stimuli. Taken together, hypertrophic stimuli induce oxidativestress through leakage of electrons from mitochondria and upregulation of Nox4 localizedon the intracellular membranes. Increased oxidative stress induces OPTM in keysignaling mechanisms, including cII HDACs, as well as mitochondrial dysfunction, therebymediating pathological hypertrophy and heart failure.S19-4Histone deacetylase 2, a novel therapeutic target of cardiac hypertrophyGwang Hyeon Eom, Young Kuk Cho, Jeong-Hyeon Ko, Sera Shin, Nakwon Choe,Yoojung Kim, Hosouk Joung, Hyung-Seok Kim, Kwang-Il Nam, Hae Jin Kee, HyunKookDepartment of Pharmacology and Medical Research Center for Gene Regulation, ChonnamNational University Medical School, Gwangju 501-746, KoreaCardiac hypertrophy is often caused by sustained hypertension, valvular diseases, ormyocardial infarction. Though initially it is an adaptive process, sustained hypertrophyoften ends up with heart failure. Histone deactylases (HDACs) repress the transcription ofdownstream target genes by posttranslational modification of histones. In contrast to theseries of studies from other groups that class II HDACs inhibit cardiac hypertrophy, weadvocate that class I HDAC is a prohypertrophic mediator; we observed that class I-selective HDAC inhibitors as well as non-specific inhibitors block cardiachypertrophy/fibrosis/heart failure in both left and right ventricles. Among class I HDACs,HDAC2 is activated by the exogenous stresses and its physical association with HSP70triggers cardiac hypertrophy. By promoter mapping analysis, we reported that Krüppel-likefactor 4 (KLF4), a novel downstream target of HDAC2, works as an anti-hypertrophicmediator. Diverse hypertrophic stimuli activate casein kinase 2 (CK2), which results in thephosphorylation of serine 394 residue of HDAC2 and subsequently in the activation ofHDAC2. Based on these results, we propose the CK2/HDAC2/HSP70/KLF4 signal pathway as a unique therapeutic target for the treatment of cardiacremodeling.S19-2Antiviral activity of Coxsackievirus B3 3C protease inhibitor inexperimental murine myocarditisSoo-Hyeon Yun¹, Yong-Chul Kim², Eun-Seon Ju¹, Byung-Kwan Lim³, Won Gil Lee²,Jin-Oh Choi¹, Duk-Kyung Kim¹, Eun-Seok Jeon¹¹Division of Cardiology, Samsung Medical Center, Sungkyunkwan University School of Medicine,Seoul, Korea,²Department of Life Science, Gwangju Institute of Science and Technology, Gwangju,Korea, ³Department of Medicine, University of California San Diego, Division of Cardiology, LaJolla, California, USABackground: We investigated the efficacy of a 3C protease inhibitor (3CPI) in murineCVB3 myocarditis model. Coxsackievirus B3 (CVB3) is a primary cause of viralmyocarditis. CVB3 genome encodes a single polyprotein that undergoes a series ofproteolytic events to produce several viral proteins. Most of this proteolysis is catalyzed bythe 3C protease (3CP). Methods and Results: Using a micro-osmotic pump, 50 mM 3CPIin 100 ul of 100% dimethyl sulfoxide (DMSO) was delivered during 72 hrs per mouse. Onday of pump implantation, mice (n = 40) were infected intraperitoneally with 106 plaqueformingunits (PFU) of CVB3. For the infected controls (n = 50), the pump was filled with100% DMSO without 3CPI. Three-week survival rate of 3CPI-treated mice wassignificantly higher than controls (90% vs 22%; P < 0.01). Myocardial inflammation, viraltiters and viral RNA levels were also reduced significantly in the 3CPI-treated groupcompared with the controls. Conclusions: This protein-based drug inhibited the activity of3C protease of CVB3, significantly inhibited viral proliferation, and attenuated myocardialinflammations, subsequent fibrosis and CVB3-induced mortality in vivo. Thus, this CVB33CPI may have a potential to be a novel therapeutic agent for acute viral myocarditis.S20-1Regulation and function of the Hippo tumor suppressor pathwayKun-Liang GuanDepartment of Pharmacology and Moores Cancer Center, University of California at San Diego,USAThe Yes-associated protein (YAP) is a transcription coactivator that plays a critical role inorgan size control by promoting cell proliferation and inhibiting apoptosis. YAP is a humanoncogene amplified or overexpressed in some human cancers. The Hippo tumorsuppressor pathway inhibits YAP through phosphorylation-induced cytoplasmic retentionand degradation. We have identified the angiomotin (AMOT) family proteins asphysiological YAP-interacting partners. AMOT inhibits YAP function by altering YAPsubcellular localization and phosphorylation. Our result identifies a new component of theHippo pathway, a novel mechanism of YAP inhibition, and has significant implications forYAP regulation in organ size control and tumorigenesis. We have also characterized thefunction of YAP in embryonic stem (ES) cells. YAP is inactivated during ES celldifferentiation as indicated by a decreased protein level and increased phosphorylation.Consistently, YAP is elevated during iPS cell reprogramming. YAP knockdown leads to aloss of ES cell pluripotency while ectopic expression of YAP prevents ES celldifferentiation in vitro and maintains stem cell phenotypes even under differentiationconditions. Moreover, YAP directly binds to promoters of a large number of genes knownto be important for stem cells and stimulates their expression. Our observations establisha critical role of YAP in maintaining stem cell pluripotency.S19-3Regulation of cytoplasmic NAD(P)+/NAD(P)H ratio by NQO1 activatoris important in vascular complicationIn-kyu LeeDepartment of Internal Medicine, Kyungpook National University, School of Medicine, Daegu,KoreaPharmacologically-induced cytoplasmic NAD(P)+/NAD(P)H ratio might stimulate the ratesof glycolysis, fatty acid oxidation through the increase mitochondrial oxidativephosphorylation and adaptive mitochondrial biogenesis. When cytoplasmicNAD(P)H:quinone oxidoreductase 1 (NQO1) is activated by exogenous compounds, thecytoplasmic NAD(P)+/NAD(P)H equilibrium is shifted towards oxidized NAD(P)+. Underthese conditions, the high NAD(P)+/NAD(P)H ratio stimulates mitochondrial oxidativephosphorylation and glycolysis and activates sirtuins. Here we show that the mechanismby which NQO1-mediated oxidation of NAD(P)H leads to enhanced mitochondrial fattyacid oxidation involves activation of AMP-activated protein kinase (AMPK). Neointimalformation, the leading cause of restenosis, is caused by proliferation of vascular smoothmuscle cells (VSMCs). In this study, we found that Bl, one of NQO1 activators whichregulates NAD(P)/NAD(P)H redox potential reduces neointimal formation after ballooninjury in vivo. Bl prevents VSMC’s proliferation caused by G1 cell cycle arrest via anAMPK dependent mechanism.S20-2Hepartic carcinogenesis by TM4SF5-mediated signalingOisun Jung¹, Minkyung Kang², Sin-Ae Lee³and Jung Weon Lee¹ , ³¹Interdisciplinary Program in Genetic Engineering, Departments of ²Biomedical Sciences, or³Pharmacy, Seoul National University, Seoul, KoreaTM4SF5 is a transmembrane glycoprotein of the transmembrane 4 L six family, a branchof the tetraspanin family and highly expressed in many types of cancers. TGFβ1-mediatedSmads activate the EGFR pathway, resulting in TM4SF5 induction and EMT. Inhibition ofSmad, EGFR, or TM4SF5 using Smad7 or small compounds blocked TM4SF5expression, EMT, and liver fibrosis in vivo. TM4SF5 induces epithelial-mesenchymaltransition (EMT) by morphological changes resulting from inactivation of RhoA mediatedby stabilized cytosolic p27kip1. TM4SF5-mediated EMT can lead to loss of contactinhibition and enhanced migration/invasion, presumably depending on cross-talksbetween TM4SF5 and integrins. An anti-TM4SF5 agent appears to target the secondextracellular domain of TM4SF5, which is important for cross-talk with integrins, leading toa blockade of TM4SF5-mediated multilayer growth and migration/invasion. Theintracellular loop of TM4SF5 directly binds the F1 lobe of the FAK FERM domain and theinteraction causes activation of FAK and activation of FAK and actin polymerization atleading edges of a migratory cell for TM4SF5/FAK interaction-enhanced metastaticpotentials. These observations suggest TM4SF5 as a membrane receptor playing criticalroles in liver fibrosis and caricnogenesis.84 Korean Society for Biochemistry and Molecular Biology