2006 Fiscal Year Final Research Report Summary
Establishment of novel therapeutic strategy for heart failure by modulating the function of cardiac contractile and relaxation proteins
| Project/Area Number |
17390224
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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, Associate 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, Chairman, 大学院・医学系研究科, 教授 (00215047)
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| Project Period (FY) |
2005 – 2006
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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)SERCA2 gene transfer by using lentiviral gene transfer system
Reduced expression of the SERCA2 gene impairs calcium handling and contractile function of the heart. We developed an SERCA2 gene transfer system using lentiviral vectors and examined the long-term effect of SERCA2 gene transfer in the rat ischemic heart failure model. Lentiviral vector containing the SERCA2 gene was infused into rat heart by hypothermic intracoronary delivery method two weeks after myocardial infarction (MI). Transduction efficiency was about 40%. Six months after transduction, echocardiogram and pressure-volume measurements revealed that SERCA2 gene transfer significantly prevented left ventricular dilation and improved systolic and diastolic function, resulting in reduction of mortality. BNP mRNA level was significantly decreased and the phosphorylation level of serine residue of PLN was increased in Lenti-SERCA2 transduced heart. Furthermore, DNA microarray analysis disclosed that SERCA2 gene transfer i
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ncreased cardioprotective gene expression but decreased genes that is known to deteriotrate heart failure progression. The SERCA2 gene was successfully integrated into the host heart, induced favorable molecular remodeling, prevented left ventricular geometrical remodeling and then improved the survival rate. These results suggest that a strategy to compensate for reduced SERCA2 gene expression by lentiviral vector serves as a positive inotropic, lucitropic and cardioprotective therapy for post-MI heart failure.
2)Discovery of 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. These compounds showed marked activation property of the SERCA2 gene transcription in the doxorubicin-induced heart failure model. These compounds were also 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 was not sufficiently high to improve heart failure in vivo.
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. Less
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Research Products
(14 results)
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[Journal Article] Increased Connective Tissue Growth Factor Relative to Brain Natriure tic Peptide as a Determinant of Myocardial Fibrosis.2007
Author(s)
Koitabashi N, Arai M, Kogure S, Niwano K, Watanabe A, Aoki Y, Maeno T, Nishida T, Kubota S, Takigawa M, Kurabayashi M
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Journal Title
Hypertension 49
Pages: 1-8
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Increased Connective Tissue Growth Factor Relative to Brain Natriuretic Peptide as a Determinant of Myocardial Fibrosis.2007
Author(s)
Koitabashi N, Arai M, Kogure S, Niwano K, Watanabe A, Aoki Y, Maeno T, Nishida T, Kubota S, Takigawa M, Kurabayashi M.
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Journal Title
Hypertension. 49
Pages: 1-8
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Carvedilol effectively blocks oxidative stress-mediated downregulation of sarcoplasmic reticulum Ca2+-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
Description
「研究成果報告書概要(和文)」より
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[Journal Article] HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box.2005
Author(s)
Doi H, Iso T, Yamazaki M, Akiyama H, Kanai H, Sato H, Kawai-Kowase K, Tanaka T, Maeno T, Okamoto E, Arai M, Kedes L, Kurabayashi M.
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Journal Title
Arterioscler Thromb Vasc Biol. 25
Pages: 2328-2334
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Carvedilol effectively blocks oxidative stress-mediated downregulation of sarcoplasmic reticulum Ca2+-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] Cardiac sarcoidosis detected by FDG-PET2005
Author(s)
Goto K, Okamoto E, Morita M, Sasamoto T, Endo M, Umezawa K, Suguta M, Kaneko Y, Nakano A, Arai M, Hasegawa A, Kurabayashi M.
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Journal Title
Nippon Naika Gakkai Zasshi. 94
Pages: 1396-1398
Description
「研究成果報告書概要(欧文)」より
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