フルテキストURL | A050064000101.pdf ( 2.1MB ) 公開日 2017-10-23
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タイトル | Heart failure-inducible suppression of protein phosphatase 1β partially prevents cardiac remodeling in experimental pressure overload-induced heart failure |
作成者 | Shiraishi, Kozo
Ikeda, Yasuhiro
Miyazaki, Yosuke
Fujimoto, Shizuka N.
Yoshimura, Koichi
Miura, Toshiro
Matsuzaki, Masunori
Yano, Masafumi
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作成者ヨミ | シライシ, コウゾウ
イケダ, ヤスヒロ
ミヤザキ, ヨウスケ
フジモト, シズカ
ヨシムラ, コウイチ
ミウラ, トシロウ
マツザキ, マスノリ
ヤノ, マサフミ
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作成者別表記 | 白石, 宏造
池田, 安宏
宮崎, 要介
藤本, 静香
吉村, 耕一
三浦, 俊郎
松﨑, 益徳
矢野, 雅文
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作成者所属 | 山口大学大学院医学系研究科(医学)
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内容記述(抄録等) | Aberrant increases in protein phosphatase 1(PP1) activity have been shown to be associated with inefficient sarcoplasmic reticulum Ca^{2+} cycling, leading to cardiac dysfunction in the failing heart. In the present study, we investigated whether BNP promoter-inducible suppression of PP1β would ameliorate progression of pressure overload-induced heart failure in mice, a clinically relevant animal model. An Adeno-associated virus 9 (AAV9) vector encoding PP1βshRNA and a negative control (NC) shRNA driven by a brain natriuretic peptide (BNP) promoter with an emerald green fluorescent protein expression (EmGFP) cassette were used to test the hypothesis. AAV9 vectors (AAV9-BNP-EmGFP-PP1βshRNA and AAV9-BNP-EmGFP-NCshRNA) were introduced into the in vivo heart via the tail vein injection (4x10^{11} GC/mice) in 8-week-old C57BL6J mice, followed by transverse aortic constriction (TAC) 2 weeks after the AAV9 vector injection. Post TAC cardiac function was sequentially assessed every 2 week by echocardiography, followed by hemodynamic assessment at 1 month. AAV9-BNP-EmGFP-PP1βshRNA treatment suppressed myocardial PP1β expression by 15% compared with the NCshRNA group (p<0.001). The fractional shortening (%FS) of the left ventricle in the PP1βshRNA-treated group was significantly larger than the NCshRNA-treated group (21%±1.0% vs. 15%±0.01, p<0.01). The ratios of heart weight (HW) / body weight (BW) and lung weight (LW) / BW in the PP1βshRNA group were significantly smaller than those of the NCshRNA group (HW/BW: 9.20±0.49 vs. 10.6±0.45 mg/g; p<0.05, LW/BW: 9.27±0.99 vs. 13.3±1.29 mg/g; p<0.05, respectively). Moreover, PP1βshRNA treatment induced a significant decrease in both LV end-diastolic pressure (28.8±1.20 to 17.2±3.93 mmHg, p<0.05) and BNP mRNA expression (40% decrease compared to the control vector treated group). Survival analysis of animals receiving PP1βshRNA treatment for 7 months showed a tendency to extend life, but this did not attain the statistical significance compared with the control vector treated group. In conclusion, heart failure-inducible molecular targeting of PP1β may be a therapeutic option for improving cardiac function and preventing cardiac remodeling in the failing heart, at least in a constrained period of a week to a month.
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本文言語 | eng
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著者キーワード | protein phosphatase 1β(PP1β)
adeno-associated virus 9 (AAV9) vector
brain natriuretic peptide (BNP) promoter
AAV9-BNP-EmGFP-PP1βshRNA
transverse aortic constriction (TAC)
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資料タイプ | text |
ファイル形式 | application/pdf |
出版者 | Yamaguchi University School of Medicine
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NII資料タイプ | 紀要論文 |
ISSN | 0513-1812
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NCID | AA00594272
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学内刊行物(紀要等) | The bulletin of the Yamaguchi Medical School |
掲載誌名 | The bulletin of the Yamaguchi Medical School |
巻 | 64 |
号 | 1-2 |
開始ページ | 1 |
終了ページ | 12 |
発行日 | 2017 |
著者版/出版社版 | 出版社版 |
リポジトリID | A050064000101 |
地域区分 | 山口大学
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URI | http://www.lib.yamaguchi-u.ac.jp/yunoca/handle/A050064000101 |