ROLE OF MICRO-RNA IN CARDIOVASCULAR BIOLOGY
I N S T I T U T E O F B I O C H E M I S T RY A N D B I O T E C H N O L O G Y
U N I V E R S I T Y O F T H E P U N J A B L A H O R E
PRESENTED BY: BASIT JABBAR
ROLL # 03
M.S. BIOTECHNOLOGY
06-05-2014
CONTENTS• What are micro-RNAs ? • Biogenesis and Mode of Action• Cardiac Development• Dilated cardiomyopathy• Angiogenesis• Cardiac hypertrophy• Atherosclerosis• Arrhythmias• Micro-RNA based therapies for cardiovascular
diseases• Potential Challenges in micro-RNA based
therapy
MICRO-RNA
• Belong to family of non-coding RNAs
• Endogenous, short (between 19 and 25 nucleotides long)
• Negative regulators of gene expression (post-transcriptional gene silencing)
• Involved in the most important cellular processes including cell growth, differentiation and apoptosis
Santovito et al., 2012. MicroRNAs and atherosclerosis: New actors for an old movie. Nut. Met.& C.D. 22 ,937-943.
BIOGENESIS AND MODE OF ACTION
Georgia & Despina, 2012. Micro-RNAs: New Biomarkers and Novel Applications for Heart Disease Prevention and Treatment, Hosp. Chron. 7, 9–15
MICRO-RNA AND CARDIOVASCULAR SYSTEM
• The cardiovascular system- transports nutrients and removing gaseous waste from the body
• Comprised of the heart, blood vessels and blood
• Cardiovascular disease is the leading cause of mortality in developed countries
• miRNAs are known to be aberrantly expressed in the cardiovascular system under some pathological conditions
• An altered expression profile of genes that are important for cardiac function
MICRO-RNA IN CARDIAC DEVELOPMENT
The most abundant miRNAs in heart are:
•miR-1• let-7•miR-133•miR-126-3p•miR-143•miR-30c•miR-22
MICRO-RNA IN CARDIAC DEVELOPMENT
Studying the role of micro-RNAs in Cardiac development
Model organisms:
Mice, Zebrafish
etc.
Creating mutation
in particular
gene
Observing the effect
DILATED CARDIOMYOPATHYKnocking out Dicer
impaired angiogenesis
under-development of the ventricular
walls
Deletion of dgcr8 gene
left ventricular malfunction
dilated cardiomyopathy
Rao et al., 2009. Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathyand heart failure. Circ Res. 105, 585–594.
Due to dilated left ventricle, the heart becomes unable to pump sufficient blood around the body.
ANGIOGENESIS• Sprouting of new blood vessels from pre-existing ones
• A normal and vital process in growth and development
• Also, wound healing and in the formation of granulation tissue
• Also required for the growth of the cancerous tissue
ANGIOGENESIS
PROANGIOGENIC mi-RNAslet7f, miR-27b, miR-126, miR-130a, miR-210, and miR-378
ANTIANGIOGENIC mi-RNAs miR-15/16, miR-20a/b, miR-92a, and miR-221/222
ANGIOGENESIS
Silencing of two key enzymes
Dicer and Drosha in murine
endothelial cells
Reduction of endothelial let-7f and miR-27b
Reduced capillary
sprouting and tube forming
ability
Kuehbacher et al., 2007. Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Cir Res. 101,59–68.
CARDIAC HYPERTROPHY
Animal models of cardiac
hypertrophy
Altered expression of
miRNAs
Upregulated miR-21, miR-23a, miR-24,
miR-125, miR-129...
Downregulated: miR-1,miR-133, miR-29, miR-30,
and miR-150
Increased heart size; lead to heart failure
Van Rooij et al., 2006. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA.103:18255–18260.
Cheng et al., 2007. MicroRNAs are aberrantly expressed in hypertrophic heart: do they play a role in cardiac hypertrophy? Am J Pathol. 170:1831–1840.
Tatsuguchi et al., 2007. Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J. Mol. Cell. Cardiol. 42, 1137–1141.
Induction of cardiac hypertrophy by miR-195. 2-week-old wild-type (WT) and transgenic mice expressing miR-195 under control of the αMHC promoter. Moderate expression levels of miR-195 (26-fold) caused cardiac hypertrophy, whereas high expression levelsof miR-195 (29-fold) caused dilated cardiomyopathy with ventricular dilation and wall thinning.
ATHEROSCLEROSIS
• Narrowing and hardening of the arteries due to build up of plaque
• Accumulation of cholesterol, triglycerides, WBCs (macrop- hages) etc..
• Involvement of miRNAs…?
Santovito et al., 2012. MicroRNAs and atherosclerosis: New actors for an old movie. Nut. Met.& C.D. 22 ,937-943.
Micrograph of an artery with atherosclerosis
Main roles for microRNAs in atherosclerotic plaque development, progression and disruption
Figure A represents a healthy artery. Figure B shows an artery with plaque build-up
ARRHYTHMIAS
• Abnormal heartbeat due to non-uniform impulse propagation
• Genetic alterations in the ion channel (Na+, K+) genes
• Leading to electrical disturbances - cardiac arrhythmias
Marban E., 2002. Cardiac channelopathies. Nat. 415, 213–218
Transmission of electrical impulses generated in SAN (pacemaker) of the heart makes atria contract first and then ventricles thus ensuring regular heart beats.
ARRHYTHMIASOver-
expression of miRNA-1
Targets GJA1(encoding connexin43, Cx43) and
KCNJ2 (encoding the K+ channel subunit,
Kir2.1)
Slowed conduction velocity and prolonged
repolarization (arrhythmia)Yang B et al., 2007. The muscle-specific
microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med.13, 486–491.
MICRO-RNA BASED THERAPIES FOR CARDIOVASCULAR DISEASES
Antisense miRNA Oligonucleotides
• Used for downregulation of miRNAs level leading to normal expression of gene
• Applicable for cardiovascular diseases
Hutva´gner et al., 2004. Sequence-specific inhibition of small RNA function. PLos Biol.2,E98.
MICRO-RNA BASED THERAPIES FOR CARDIOVASCULAR DISEASES
miRNA Mimics
• Enhancement of miRNA expression that are downregulated in cariovascular diseases
• miR-9 is downregulated in cardiac hypertrophy
• miRNA mimic for miR-9 in cardiac hypertrophy rat model led to attenuation of cardiac hypertrophy and improvement of cardiac function
Wang K, Long B, Zhou J, Li PF. miR-9 and NFATc3 regulate myocardin in cardiac hypertrophy.J Biol Chem2010;285:11903-11912
Eva et al., 2008. Toward Micro-RNA Based Therapeutics for Heart Disease : The Sense in Antisense. Circ Res. 103, 919-928.
POTENTIAL CHALLENGES IN MICRO-RNA BASED THERAPY
CHAL
LENG
ES
Delivery of the miRNA modulator
Off-target effects of unintended or unidentified targets of a miRNA
Toxicity of the miRNA modulator
A single miRNA can have both beneficial and pathogenic effects
Eva et al., 2008. Toward Micro-RNA Based Therapeutics for Heart Disease : The Sense in Antisense. Circ Res. 103, 919-928.
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