2004 Fiscal Year Final Research Report Summary
Development of novel therapeutic strategy for heart failure by improving Ca2+ transport function of sarcoplasmic reticulum
| Project/Area Number |
15590717
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Gunma University |
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Principal Investigator |
ARAI Masashi Gunma University, Graduate School of Medicine Department of Medicine and Biological Science, Assistant Professor, 医学部, 講師 (60270857)
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| Co-Investigator(Kenkyū-buntansha) |
KURABAYASHI Masahiko Gunma University, Graduate School of Medicine Department of Medicine and Biological Science, Professor and Chairman, 医学系研究科, 教授 (00215047)
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| Project Period (FY) |
2003 – 2004
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| Keywords | SERCA2 / phospholamban / sarcoplasmic reticulum / gene therapy / RNA interference / gene transcription / heart failure / calcium |
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| Research Abstract |
1)New pharmacological agent which activates the transcription of the SERCA2 gene
We have screened over 80,000 chemical compounds and picked up 9 compounds that activate the transcription of the SERCA2 gene in H9C2 cardiac cells. These compounds are applied to rats under heart failure induced by aortic banding and the effect of these compounds on the activation of the SERCA2 mRNA levels examined. One of these compounds increased the SERCA2 mRNA level by 20%. However, because the effect is not sufficiently high to improve heart failure in vivo, we are now further searching the compound library to find out more potent one.
2)SERCA2 gene therapy
We have developed lentiviral gene transfer system bearing human SERCA2 cDNA. We introduced the gene construct into rat coronary artery of failing heart induced by myocardial infarction and examined the effect of SERCA2 gene introduction on the cardiac function of failing heart. Seven days after gene transfer, SERCA2-transfected demonstrated the signif
… More
icant increase of the fractional shortening from 16.5% to 26%, whereas the GFP, a non-functioning protein for contraction of heart, gene transfer did not significantly improve the fractional shortening (from 16 to 19%). These changed were corresponded with the upregulation of the SERCA2 mRNA and protein levels, which suggests the feasibility of the lentiviral SERCA2 gene transfer system as a therapeutic modality of heart failure.
3)Development of phospholamban ablation method
Double strand 21 ribonucleotide sequence specific for coding region of phospholamban gene was introduced into rat neonatal cardiac myocytes using HVJ envelope. The effect of phospholamban siRNA was highly gene specific for target mRNA and reduced its mRNA level to 10% of control group. Importantly, Ca2+ uptake kinetics was shifted to increase the efficiency by 38%. These beneficial effect of phospholamban RNAi was also demonstrated in the hydrogen peroxide-induced failing heart model. Decreased Ca2+ uptake was restored in the phospholamban ablation group.
Our research suggests that genetic modulation of Ca2+ transporting protein has a therapeutic benefit in the treatment of heart failure. Less
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[Journal Article] Carvedilol effectively blocks oxidative stress-mediated downregulation of sarcoplasmic reticulum Ca(2+)-ATPase 2 gene transcription through modification of Sp1 binding.2005
Author(s)
Koitabashi N, Arai M, Tomaru K, Takizawa T, Watanabe A, Niwano K, Yokoyama T, Wuytack F, Periasamy M, Nagai R, Kurabayashi M.
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Journal Title
Biochem Biophys Res Commun. 328
Pages: 116-124
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The PAI-1 gene as a direct target of endothelial PAS domain protein-1 in adenocarcinoma A549 cells.2004
Author(s)
Sato M, Tanaka T, Maemura K, Uchiyama T, Sato H, Maeno T, Suga T, Iso T, Ohyama Y, Arai M, Tamura J, Sakamoto H, Nagai R, Kurabayashi M.
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Journal Title
Am J Respir Cell Mol Biol. 31
Pages: 209-215
Description
「研究成果報告書概要(欧文)」より
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[Book] 心臓ナビゲーター2004
Author(s)
新井 昌史
Total Pages
2
Publisher
メディカルレビュー社
Description
「研究成果報告書概要(和文)」より
