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フルテキストURLA050064000101.pdf ( 2.1MB ) 公開日 2017-10-23
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
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
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
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.
著者キーワードprotein phosphatase 1β(PP1β)
adeno-associated virus 9 (AAV9) vector
brain natriuretic peptide (BNP) promoter
transverse aortic constriction (TAC)
出版者Yamaguchi University School of Medicine
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