1. Research on microRNAs Regulating Cardiac Arrhythmias 艾 静 杨宝峰 哈尔滨医科大学药理教研室 Department of Pharmacology, Harbin Medical University State-Province Key Laboratories

2. 2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●  In China, about 3 million people died each year of cardiovascular disease, approximately 45% of the total mortality.  About 600,000 cardiogenic sudden death occurred each year, more than 90% induced by malignant arrhythmias. Harbin Medical University Background

3. 3 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Ischemia Hypertrophy Atrial fibrillation Heart failure Arrhythmias Arrhythmias is the common pathogenesis of heart diseases

4. 4 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●  Antiarrhythmic drugs were not very efficient, the total effective rate was only 30%-60%, and incidence of proarrhythmic side effect >3%.

5. 5 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Mechanisms

6. 6 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Medicine IKr/HERG IK1 IKr/HERG 1. Ion channels K + channel blockers Ca 2+ channel blockers Na + channel blockers Infarction Healthy IK ICaINa Mechanisms of antiarrhythimic drugs 2. Receptors β-adrenoceptor blockers 3. Genes 4. RAAS

7. MicroRNAs Cell proliferation Differentiation Apoptosis Metabolism Stress Development

8. 8 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● MicroRNAs and Arrhythmias

9. 9 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Atrial fibrillation (AF)

10. 10 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ECG recordings of sinus rhythm and AF Electriac Remodeling Structural Remodeling Autonomomic Remodeling

11. 11 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Atrial Remodeling Electriac Remodeling

12. 12 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Atrial Remodeling- Electriac Remodeling miR-26 KCNH2/Ikr miR-1 EADs DADs NCX/Na + -Ca 2+ exchanger miR-27miR-214miR-30 HCN2/If HCN4/If miR-133 CACNA1C/Cav1.2 CACNB1/Cavβ1 miR-328 miR-133

13. 13 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Atrial Remodeling- Structural Remodeling miR-30 miR-29 miR-133 mir-590

14. 14 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Atrial Remodeling- Autonomomic Remodeling Parasympathetic nervous systerm Sympathetic nervous systerm I kAch I Ca(L) KCNJ3/Kir3.1 KCNJ5/Kir3.4 miR-30,miR-150 miR-1

15. 15 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● miR-328 miR-1, miR-26 miR-133, miR-590 miR-29, miR-30 Electriac Remodeling Structural Remodeling Autonomomic Remodeling Fibrosis Apoptosis Ionic remodeling Ca 2+ - handling MicroRNAs and AF

16. 16 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Schematic summary of regulation of various genes pertinent to AF by miRNAs based on published studies

17. 17 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Malignant ventricular arrhythmias

18. 18 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Abnormal expression of miRNAs in hypertrophy and myocardial infarction miR-499

19. 19 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● miRNAs regulate target genes in APD SCN5A/INa miR-1 miR-195 KCND2/Ito KCND3/Ito miR-1,miR-133 KCNQ1/Iks KCNE1/Iks miR-133 miR-1 KCNJ2/Ik1 miR-1 miR-26 KCNH2(HERG)/Ikr KCNE2/Ikr miR-133 miR-1 miR-133 miR-328 CACNA1C/Cav1.2 CACNB1/Cavβ1 KCNJ2/Ik1 miR-1

20. 20 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 不同的 microRNAs 调节一个靶基因发挥作用 ; 一个 microRNAs 调节多个靶基因发挥作用。 MicroRNAs 通过调节 APD 过程中不同通道蛋白 参与心律失常的发生。 调节方式：

21. 21 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Arrhythmias (Sudden death) Harbin Medical University Myocardial Infarction miR-1 Role of miRNA-1 in malignant Arrhythmias conduction GJA1/Cx43/I j repolarization KCNJ2/Kir2.1/I K1 I k1 Ca 2+ handling B56a/RyR2 SR Hsp60, Hsp70 Apoptosis structure cMLCK/CaM

22. 22 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● MicroRNA-1 通过调节不同的生物学过程参与心 律失常的发生和发展过程。 miR-1 miR-133 miR-328 miR-26 miR-30 miR-499 miR-21 miR-195 miR-181

23. 23 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Arrhythmias (Sudden death) conductionrepolarizationstructureCa 2+ handlingdispersionfibrosis Harbin Medical University Myocardial Infarction Atrial Fibrosis Hyperlipidemia Hypertrophy Heart Failure Diabetic Cardiomyopathy miR-1 GJA1/Cx43/I j KCNH2/ERG/I Kr KCNJ2/Kir2.1/I K1 miR-133/590 miR-328 TGF-βsignalingcMLCK/CaMCav1.2/I Ca miR-26 CACNAB1/Cavβ1Calcineurin Summary of role of miRNAs in malignant heart diseases

24. 24 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Autonomic nervous systerm regulation of heart function microRNAs

25. 25 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● M 3 R↑ miR-1↓ Kir2.1/I K1 ↑RMP VT↓ Sudden death↓

26. 26 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Harbin Medical University

27. 27 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Harbin Medical University

28. 28 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Harbin Medical University Lab members

29. 29 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●