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Lee, Hae-Ahm,Lee, Dong-Youb,Cho, Hyun-Min,Kim, Sang-Yeob,Iwasaki, Yasumasa,Kim, In Kyeom American Heart Association, Inc. 2013 Circulation research Vol.112 No.7
<P><B><U>Rationale:</U></B></P><P>Inhibition of histone deacetylases (HDACs) results in attenuated development of hypertension in deoxycorticosterone acetate–induced hypertensive rats and spontaneously hypertensive rats. However, the molecular mechanism remains elusive.</P><P><B><U>Objective:</U></B></P><P>We hypothesized that HDAC inhibition attenuates transcriptional activity of mineralocorticoid receptor (MR) through its acetylation and prevents development of hypertension in deoxycorticosterone acetate–induced hypertensive rats.</P><P><B><U>Methods and Results:</U></B></P><P>Expression of MR target genes was measured by quantitative real-time polymerase chain reaction. Recruitment of MR and RNA polymerase II on promoters of target genes was analyzed by chromatin immunoprecipitation assay. Live cell imaging was performed for visualization of nuclear translocation of MR. MR acetylation was determined by Western blot with anti-acetyl-lysine antibody after immunoprecipitation with anti-MR antibody. Transcriptional activity of MR was determined by luciferase assay. For establishment of a hyperaldosteronism animal, Sprague-Dawley rats underwent uninephrectomy and received subcutaneous injection of 40 mg/kg per week of deoxycorticosterone acetate and drinking water containing 1% NaCl. Treatment with a HDAC class I inhibitor resulted in reduced expression of MR target genes in accordance with reduced recruitment of MR and RNA polymerase II on promoters of target genes. HDAC inhibition promoted MR acetylation, leading to decreased transcriptional activity of MR. Knockdown or inhibition of HDAC3 resulted in reduced expression of MR target genes induced by mineralocorticoids.</P><P><B><U>Conclusions:</U></B></P><P>These results indicate that HDAC inhibition attenuates transcriptional activity of MR through its acetylation and prevents development of hypertension in deoxycorticosterone acetate–induced hypertensive rats.</P>
Lee, Hae-Ahm,Lee, Dong-Youb,Lee, Hyo-Jung,Han, Hyung Soo,Kim, InKyeom SAGE Publications 2012 Journal of the renin-angiotensin-aldosterone syste Vol.13 No.1
<P>The (pro)renin receptor [(P)RR] non-proteolytically, through conformational change, activates prorenin which can convert angiotensinogen to angiotensin I in addition to the classic conversion of angiotensinogen to angiotensin I by circulating renin. Since renal (P)RR is upregulated in hypertension and implicated in the pathogenesis of malignant hypertension, we hypothesized that (pro)renin receptor promoter is enriched with activating histone codes in the kidney of spontaneously hypertensive rats (SHR).</P>
Lee, Eunjo,Song, Min-ji,Lee, Hae-Ahm,Kang, Seol-Hee,Kim, Mina,Yang, Eun Kyoung,Lee, Do Young,Ro, Seonggu,Cho, Joong Myung,Kim, Inkyeom The Korean Society of Pharmacology 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.5
CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.
Drug/ion co-delivery multi-functional nanocarrier to regenerate infected tissue defect
Lee, Jung-Hwan,El-Fiqi, Ahmed,Mandakhbayar, Nandin,Lee, Hae-Hyoung,Kim, Hae-Won IPC Science and Technology Press 2017 Biomaterials Vol.142 No.-
<P><B>Abstract</B></P> <P>Regeneration of infected tissues is a globally challenging issue in medicine and dentistry. Common clinical therapies involving a complete removal of infected areas together with a treatment of antimicrobial drugs are often suboptimal. Biomaterials with anti-bacterial and pro-regenerative potential can offer a solution to this. Here we design a novel nanocarrier based on a mesoporous silicate-calcium glass by doping with Ag ions and simultaneously loading antimicrobial drugs onto mesopores. The nanocarriers could controllably release multiple ions (silver, calcium, and silicate) and drugs (tetracycline or chlorohexidine) to levels therapeutically relevant, and effectively internalize to human dental stem cells (∼90%) with excellent viability, ultimately stimulating odontogenic differentiation. The release of Ag ions had profound effects on most oral bacteria species through a membrane rupture, and the antibiotic delivery complemented the antibacterial functions by inhibiting protein synthesis. Of note, the nanocarriers easily anchored to bacteria membrane helping the delivery of molecules to an intra-bacterial space. When administered to an infected dentin-pulp defect in rats, the therapeutic nanocarriers effectively regenerated tissues following a complete bacterial killing. This novel concept of multiple-delivering ions and drug can be extensively applied to other infectious tissues that require relayed biological functions (anti-bacterial then pro-regenerative) for successful healing.</P>
Lee, Hae-Ahm,Lee, Eunjo,Do, Ga Young,Moon, Eun-Kyung,Quan, Fu-Shi,Kim, Inkyeom Elsevier 2019 BIOMEDICINE AND PHARMACOTHERAPY Vol.109 No.-
<P><B>Abstract</B></P> <P>Inhibition of histone deacetylase (HDAC) suppresses inflammation of pancreatic islets and apoptosis of β-cells. However, the underlying molecular mechanism is unclear. In the present study, we demonstrate that MGCD0103 (MGCD), an HDAC inhibitor, protects the pancreas from streptozotocin (STZ)-induced oxidative stress and cell death. Sprague-Dawley rats were intraperitoneally injected with STZ (40 mg/kg) to induce type I diabetes. MGCD (10 μg/day) was infused with osmotic mini-pump for 4 weeks. Pancreatic insulin and macrophage infiltration were analyzed by immunohistochemistry. Cellular level of reactive oxygen species (ROS) was evaluated with fluorescence-activated cell sorting. Tetramethylrhodamine ethyl ester was used to analyze mitochondrial membrane potential. Activation of caspase-3 was analyzed by western blotting. Chromatin immunoprecipitation was performed to investigate the binding affinity of specificity protein 1 (SP1) on the promoters of target genes. mRNA expression was analyzed by quantitative real-time polymerase chain reaction. As a result, we found that MGCD infusion ameliorated STZ-induced hyperglycemia, islet deformation, decreased insulin level, and macrophage infiltration. STZ injection promoted the production of ROS, which induced caspase activity and β-cell death. 4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL), a mimetic of superoxide dismutase (SOD), reduced STZ-induced caspase activity and β-cell death. MGCD treatment increased SOD expression and histone acetylation level on promoters. Infusion of MGCD promoted acetylation of SP1 and its enrichment on SOD promoters. Thus, MGCD protects pancreatic β-cells from STZ-induced oxidative stress and cell death through the induction of antioxidant enzymes such as SODs.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Eunjo Lee,Min-ji Song,Hae-Ahm Lee,Seol-Hee Kang,Mina Kim,Eun Kyoung Yang,Do Young Lee,Seonggu Ro,Joong Myung Cho,Inkyeom Kim 대한생리학회-대한약리학회 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.5
CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinkingwater containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (<i>Nppa</i>) and atrial natriuretic peptide B (<i>Nppb</i>) in addition to fibrotic genes such as <i>Collagen-1, Collagen-3</i>, connective tissue growth factor (<i>Ctgf </i>),and <i>Fibronectin </i>were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.