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Role of microRNAs in heart diseases

Role of microRNAs in heart diseases. miRNA induced myocardial interstitial fibrosis. Baofeng Yang, Zhiguo Wang, Yanjie Lu, Zhenwei Pan Department of Pharmacology, Harbin Medical University State-Province Key Laboratories.

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Role of microRNAs in heart diseases

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  1. Role of microRNAs in heart diseases miRNA induced myocardial interstitial fibrosis Baofeng Yang, Zhiguo Wang, Yanjie Lu, Zhenwei Pan Department of Pharmacology, Harbin Medical University State-Province Key Laboratories

  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. Myocardial interstitial fibrosis can result in structural remodeling, and induce lethal arrhythmias. Background Harbin Medical University

  3. Ischemia Atrial fibrillation Ventricular tachycardia Myocardial fibrosis Structural remodeling Heart failure Hypertrophy Fibrosis is a characteristic of all forms of cardiac diseases of different origins

  4. Mechanism of myocardial interstitial fibrosis? Electrical remodeling ? Heart diseases Structural remodeling Myocardial fibrosis

  5. Control Nicotine (50) Induction of atrial fibrosis by nicotine in dogs Collagen content Fibrosis

  6. Induction of atrial fibrosis by nicotine in dogs TGF-β1 TGF-βR2 CTGF Nicotine (50) Nicotine (50) Nicotine (5) Nicotine (50) Nicotine (5) Nicotine (5) Control Control Control 70kDa 25kDa 38kDa GAPDH GAPDH GAPDH

  7. Intracardiac pacing induced fibrosis Collagen content Control Pacing Fibrosis

  8. Intracardiac pacing induced fibrosis A B C

  9. Myocardial ischemia induced fibrosis Infarction area Collagen content Sham (LV) MI (Border zone) Fibrosis

  10. Myocardial ischemia induced fibrosis NIZ IZ NIZ IZ

  11. How fibrosis related signaling pathway was regulated ?

  12. Alteration of expression of miRNAs in different fibrosis models Canine A-TP Canine nicotine Rat MI

  13. Alteration of expression of miRNAs in different cardiac fibrosis patients Atrial fibrillation patients Smoking patients CAD patients

  14. miR-133 and miR-590 regulate TGF-β1 and TGF-βRII protein expression TGF-β1 TGF-βRII

  15. miR-133 and miR-590 target TGF-β1 and TGF-βRII 3’UTR miR-133 & TGF-β1 3’UTR miR-590 & TGF-βRII 3’UTR

  16. Cardiac-specific overexpression of miR-328 causes fibrosis and cardiac dysfunction Collagen content WT TG Fibrosis

  17. Knockdown of miR-328 protective against fibrosis induced by MI MI Border zone Infarction area WT miR-328 Knockdown WT Fibrosis miR-328 Knockdown

  18. MiR-328 regulates collagen production Collagen

  19. Elevated TGF-β signals in TG mice heart TGF-β1 M-miR-328 miR-328 +AMO-328 NC 12KDa TGF-β1 GAPDH 36KDa

  20. Elevated TGF-β signals in TG mice heart P-smad2/3 miR-328 M-miR-328 +AMO-328 NC p-smad2/3 60KDa GAPDH 36KDa

  21. MiR-328 targets directly to TGFBRIII TGF-βRIII

  22. MiR-328 targets directly to TGFBRIII Luciferase: miR-328 targets TGFBRIII 3’UTR

  23. miR-328 overexpression incuced fibrosis and triggered AF Canine atrium Mice ECG

  24. miR-328 targets at CACNA1C and CACNB1

  25. miR-328 overexpression caused cardiac fibrosis Ischemia Pacing Fibrosis miR-328 Collagen AF TGF-β1 TGFBRIII TGFBRI/II Under certain pathological conditions, level of miR-328 is increased and triggers down-regulation of its target gene TGFBR3 in cardiac fibroblast, which is leading to production of collagens and formation of cardiac fibrosis. Harbin Medical University

  26. miRNAs and cardiac fibrosis Hypertrophy Heart Failure Diabetic Cardiomyopathy Myocardial Infarction Atrial Fibrillation miR-590 miR-328 miR-133 Cav1.2/ICa Calcineurin CACNAB1/Cavβ1 TGF-βRII TGFβ1 TGF-βRIII repolarization structure Ca2+ handling dispersion collagen Fibrosis Circulation, 2010; Cardiovasc Res, 2009a; Hypertension, 2009; BJP, 2009a, 2009b Harbin Medical University

  27. Problems in clinical application of miRNAs • Effective drug delivery way • Specific action on the target tissue • Selection of miRNAs carriers

  28. Advances in clinical application of miRNAs • Nanotechnology：American scientists used nano-particles to wrap miRNAs, and then passes on the outer package layer of protein. This technique can effectively treat mice with the Ewing's sarcoma. • Locked nucleic acids technique：Santaris Pharma, a Danish company has commenced a Phase I human volunteer trial of SPC3649 (LNA-antimiRTM-122, developed as a new approach to treathepatitis C infection), the world's first miRNA medicine to be tested in man. • Cholesterol-conjugated AMO：Complementary AMOtargeted oncogene miRNA (eg miR-155) may cause carcinogenic miRNA inactivation, slow tumor growth. AMO combined with cholesterol was taken as a new treatment way to inhibit oncogene miRNA in mice.

  29. Lab members Yanjie Lu Deli Dong Xu Gao Hongli Shan Jing Ai Baoxin Li Guofen Qiao Chaoqian Xu Wenfeng Chu Benzhi Cai Yong Zhang Zhiguo Wang Xiaobin Luo Zhenwei Pan Jiening Xiao Huixian Lin Ning Wang Lihua Sun Yan Liu Yunlong Bai Dongfang Gu Ying Zhang Harbin Medical University

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