微RNA-133和心肌肥厚钙调磷酸酯酶控制的相互抑制(英文)课件

1、Reciprocal Repression between MicroRNA-133 and Calcineurin Controls Cardiac Hypertrophy: A Novel Mechanism for Progressive Cardiac HypertrophyDe-Li Dong, Yan-Jie Lu, Bao-Feng Yang(董德利 吕延杰 杨宝峰)Department of PharmacologyHarbin Medical University, P.R.China Aug.20-22,2009.Dalian BackgroundCalcineurin/N

2、FAT pathway induces Cardiac Hypertrophy Calcineurin activation in cardiac hypertrophyDecreased miR-133 expression in cardiac hypertrophy Overexpression of miR-133 inhibits cardiac hypertrophy Inhibition of miR-133 induces cardiac hypertrophyAug.20-22,2009.Dalian 1. Calcineurin-Dependent Cardiac Hype

3、rtrophyJeffery D. Molkentin et al. Cell,1998; 93,215228. Aug.20-22,2009.Dalian 1. Calcineurin-Dependent Cardiac HypertrophyJeffery D. Molkentin et al. Cell,1998; 93,215228. Aug.20-22,2009.Dalian 1.Calcineurin-Dependent Cardiac HypertrophyJeffery D. Molkentin et al. Cell,1998; 93,215228. Aug.20-22,20

4、09.Dalian Overexpression of calcineurin in mouse causes sudden cardiac death associated with decreased density of K channelsDeli Dong. et al. Cardiovascular Research 57 (2003) 320332Aug.20-22,2009.Dalian 2. Calcineurin Activation in cardiac hypertrophyHae W. Lim et al.Circulation. 2000;101:2431-2437

5、.Aug.20-22,2009.Dalian 5. Overexpression of miR-133 inhibits cardiac hypertrophyCar A et al. Nat Med. 2007;13(5):613-8. Aug.20-22,2009.Dalian 6. Inhibition of miR-133 induces cardiac hypertrophyCar A et al. Nat Med. 2007;13(5):613-8. Aug.20-22,2009.Dalian Hypothesis: Interaction between miR-133 and

6、calcineurin in cardiac hypertrophy? Calcineurin is the target of miR-133; The expression of miR-133 is regulated by calcineurin/NFAT signaling pathway.CalcineurinmiR-133Cardiac hypertrophyAug.20-22,2009.Dalian 1. miR-133 Targets CalcineurinFigure 4. Effects of miR-133 on calcineurin protein levels (

7、n=5), mRNA level (n=5) and cell area (The number of cells was in brackets) in cardiomyoctes treated with PE (50M). A B C Aug.20-22,2009.Dalian Results: Calcineurin/NFAT Signaling Regulates miR-133 ExpressionFig.5. Calcineurin inhibitor CsA inhibited cardiac hypertrophy induced by transverse aortic c

8、onstriction in mice.Sham TAC TAC+CsA Aug.20-22,2009.Dalian A B Results: Calcineurin/NFAT Signaling Regulates miR-133 ExpressionFig.6. Calcineurin inhibitor CsA inhibited cardiac hypertrophy (The number was in brackets), calcineurin expression (n=5) and activity (n=5). *P0.01 vs Control; #P0.01 vs TA

9、C. Aug.20-22,2009.Dalian A B C Results: Calcineurin/NFAT Signaling Regulates miR-133 ExpressionFig.7. CsA restored the decreased miR-133 expression but not the increased miR-195 expression in TAC-induced hypertrophic heart. *P0.01 vs Control. # P0.01 vs TAC; n=5. Aug.20-22,2009.Dalian A B Results: C

10、alcineurin/NFAT Signaling Regulates miR-133 Expression Fig.9. CsA inhibited hypertrophy (The number was in brackets), calcineurin expression (n=5) and activity (n=5) in cardiomyocytes treated with PE (50M). *P0.01 vs Control. # P0.01 vs PE. Aug.20-22,2009.Dalian A B C Results: Calcineurin/NFAT Signa

11、ling Regulates miR-133 ExpressionFig.10. CsA alleviated the decreased miR-133 expression in PE-treated cardiomyocyes. *P0.01 vs Control. #P0.05 vs PE; n=5. Aug.20-22,2009.Dalian Results: Calcineurin/NFAT Signaling Regulates miR-133 ExpressionFig.11. Calcineurin/NFAT-dependent Regulation of miR-133. (A) Antisense-A ODNs increased the expression of miR-133 in cultured cardiomyocytes. *P0.01 vs Control; n=4. (B) NFAT decoy ODNs increased the expression of miR-133 in cultured cardiomyocytes. *P0.01 vs Control; n=5.Aug.20-22,2009.Dalian