role of micrornas in atrial fibrillation
DESCRIPTION
Role of microRNAs in Atrial Fibrillation. Baofeng Yang Yanjie Lu Department of Pharmacology, State-Province Key Laboratories, Harbin Medical University. Atrial fibrillation (AF), the most common cardiac arrhythmia. - PowerPoint PPT PresentationTRANSCRIPT
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Role of microRNAs in Atrial FibrillationRole of microRNAs in Atrial Fibrillation
Baofeng Yang
Yanjie Lu
Department of Pharmacology, State-Province Key Laboratories, Harbin Medical University
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Atrial fibrillation (AF), the most common cardiac arrhyt
hmia.
AF increases with age, occurs in 8% of people over 80,
and causes a third of all strokes.
AF can cause or exacerbate heart failure.
Harbin Medical University
Background
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Sinus rhythm Atrial fibrillation
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Positive feedback-loops of atrial remodeling in AF
Cardiovascular Research 54 (2002) 230–246
AF begets AF
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Involvement of microRNAs in heart
Myocyte growth, integrity of the ventricular wall, contractility, angiogenesis, gene expression, maintenance of cardiac rhythm.
In multiple forms of heart disease, hypertrophy, fibrosis, arrhythmia etc.
microRNAs (miRNAs) as biomarker for cardiovascular disease.
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miRNAs and cardiac fibrosis
Journal of Cardiovascular Pharmacology. 2010, 454-459
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Nicotine increases AF vulnerability in dogs
Cardiovascular Research (2009) 83, 465–472
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Induction of atrial fibrosis by nicotine in dogs
Control Nicotine (50)
Fibrosis
Collagen content
Cardiovascular Research (2009) 83, 465–472
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Effects of nicotine on expression of TGF-b1 and TGF-bRII in cultured canine atrial fibroblasts
A B
Cardiovascular Research (2009) 83, 465–472
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Nicotine-induced alteration of expression of miRNAs in cultured atrial fibroblasts and atrial tissue
Cardiovascular Research (2009) 83, 465–472
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miR-133 and miR-590 regulate TGF-β1 and TGF-βRII protein expression
TGF-β1 TGF-βRII
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Effect of miR-133 and miR-590 on collagen production in cultured canine atrial fibroblasts
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Intracardiac pacing induced fibrosis
Control
Fibrosis
Pacing
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Myocardial ischemia induced fibrosis
Sham (LV) MI (Border zone)
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Alteration of miRNAs profiling in A-TP dogs
Canine A-TP
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Alteration of expression of miRNAs in AF patients
Atrial fibrillation patients
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miR-328 targets directly to TGFBRIII
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miR-328 targets directly to TGFBRIII
Luciferase: miR-328 targets TGFBRIII 3’UTR
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miR-328 targets directly to TGFBRIII
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p-smad2/3
GAPDH 36KDa
NC
miR
-328
+AM
O-3
28M
-miR
-328
60KDa
Elevated TGF-β signals by miR-328
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miR-328 regulates collagen production in fibolasts
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Knockdown of miR-328 protective against fibrosis induced by MI
antagomiR-328
MI
MI Border zone
MI A-328
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Collagen
TGFBRI/IITGFBRIII
Pacing
miR-328
Fibrosis
TGF-β1
AF
Harbin Medical University
Signaling of miR-328-induced cardiac fibrosis
Ischemia
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miRNA and ion channels
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Regulation of channels by miRNAs
miR-1
Kir2.1 (KCNJ2)Cx43 (GJA1)
miR-26
ICaL (CACNA1C CACNB1)
miR-328
IKr (KCNH2)
miR-133
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Alteration of electrophysiology in A-TP dogs
C
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miRNA expression profiling in atrial samples from a canine model of AF and AF patients
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miR-328 overexpression triggered AF
Canine atrium Mice ECG
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Alignment of the sequences of miR-328 with the 3‘-UTRs of CACNCA1 and CACNB1
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miR-328 targets at CACNA1C and CACNB1
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miR-328 affected ICa-L currents
A B
miR-328 TG mice miR-328 TG mice
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miR-328 targets at CACNA1C and CACNB1
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miR-328 targets at CACNA1C and CACNB1
A B
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miR-328 did not affect IK1 and Ito
A B
Circulation 2010 Dec 7;122(23):2378-87
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miRNA Perspective
Biomarkers in disease diagnosis and
progression
Potential therapeutic targets by block
ing or mimicking miRNA activities
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Harbin Medical University
Team members
Baofeng Yang
Yanjie Lu
Xu Gao
Hongli Shan
Jing Ai
Baoxin Li
Guofen Qiao
Chaoqian Xu
Wenfeng Chu
Benzhi Cai
Yong Zhang
Deli Dong
Zhenwei Pan
Jiening Xiao
Huixian Lin
Ning Wang
Lihua Sun
Yan Liu
Zhiguo Wang
Yunlong Bai
Dongfang Gu
Ying Zhang
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1. APD:action potential duration; AFCl: AF cycle length; θ: conduction velocity;WL: wave length.2. in plasma samples isolated from patients with acute myocardial infarction, ca
rdiac myocyte-associated mature miR-1, miR-208b and -499 were greatly elevated when compared with controls
3. These findings suggest that miR-24 has a critical role in cardiac fibroblast function and cardiac fibrosis after MI through a furin–TGF-β pathway. MicroRNA-24 Regulates Cardiac Fibrosis after Myocardial Infarction
JCMM. 1582-4934.2012.
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FIGURE 1. miRNAs implicated in cardiac fibrosis. Different injuries to the heart induce hypertrophy and fibrosis at least in part by microRNA-mediated mechanisms. Upregulation of miR-21 in fibroblasts downregulates Spry1, which derepresses ERK/MAP kinase signaling and results in enhanced fibroblast survival and extracellular matrix deposition. Downregulation of PTEN by miR-21 in fibroblasts may increase matrix metalloproteinase-2 expression. Downregulation of miR-29 in fibroblast may simulate fibrosis by enhanced collagen and fibrillin expression, whereas miR-30 downregulation derepresses CTGF expression, a powerful stimulator of cardiac fibrosis. CTGF expression is also increased in cardiomyocytes after downregulation of miR-133. miR-590 downregulation in cardiomyocytes increases TGF beta expression, which is also linked to fibrosis by stimulating CTGF expression by downregulation of miR-30 and miR-133 expression. Secretion of FGF-2 by fibroblasts may stimulate cardiomyocyte hypertrophy.
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5 and 50 nmol/L kg (i.v.) nicotine yielded blood levels of 50 and500 nmol/L, respectively, at 1 h after administration (administrated for 30 days).
It has been shown that the average blood concentration of nicotine in regular smokers is 220 nmol/L and that the level can reach 440 nmol/L after consumption of a single cigarette
Mecamylamine (MA, a centrally acting antagonist selective for non-a7-nAChRs, a-Bungarotoxin (a-BTX, an antagonist selective to a7 nicotinic acetylcholinereceptors, a7-nAChRs, Hexamethonium (HEX, a non-competitive antagonist to peripherally acting or ganglionic nAChR), SB-431542, a small molecule inhibitor of TGF-bRI
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How fibrosis related signaling pathway was regulated by miRNA?
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Model showing positive regulation of immediate-early TGF-ß signaling resulting in the induction of ECM. LTBP/LAP = latent TGF-ß binding protein; SBE = Smad binding element; TGF-ßR = TGF-ß receptor; TFBE = transcription factor binding element, whose identity depends on the identity of the TGF-ß-responsive promoter, P = phosphorylated protein. LTBP/LAPs are cleaved from latent TGF-ß, releasing active TGF-ß. TGF-ß then binds to TGF-ßR I and II. TGF-ßRI phosphorylates Smad3, which binds to Smad4. The resultant complex migrates into the nucleus to interact with the SBE and basal transcription factors binding to the TFBE. Activity of the Smad/basal transcription factor complex is modified by other signaling cascades depending on the promoter of interest. The net result is the induction of gene expression, including the elevated expression of genes encoding extracellular matrix. For details, see text._art;1>
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