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reduced heart rate and prolonged ventricular depolarization. The cardiac transcription
factor Irx5, a known regulator of cardiac repolarization, is a direct target of miR-1-2
and may be directly responsible for this electrical conduction defect (Zhao et al.
2007
). Knockdown of miR-1 prevents heart arrhythmias, while miR-1 overexpres-
sion caused cardiac arrhythmias in normal and infarcted rat hearts. Both the gene
encoding the cardiac gap junction channel connexin43 and the gene encoding
Kir2.1, the principle pore-forming subunit for the inwardly rectifying potassium ion
current IK1, are targeted by miR-1. miR-1 levels are increased in patients who have
had a myocardial infarction as well as in a rat model of myocardial infarction.
These results strongly suggest that a tight regulation of miR-1 levels is crucial for
the maintenance of normal cardiac conduction and raise hope that miR-1 inhibition
after myocardial infarction could reduce sudden death.
miRNA-Based Approach for Reduction of Hypercholesterolemia
Hypercholesterolemia is an important risk factor for cardiovascular disease, and
liver plays an important role in cholesterol metabolism. Antisense inhibition is a
powerful technique in regulating the function of miRNAs in the liver. To determine
the role of miR-122 in the adult liver, Isis scientists inhibited miR-122 with an
antisense oligonucleotide in mice (Esau et al.
2006
). The antisense inhibition of
miR-122 in normal and high fat-fed mice resulted in a significant improvement in
numerous metabolic and cardiovascular risk factors as evidenced by reduced
plasma cholesterol levels, increased hepatic fatty acid oxidation, decreased hepatic
fatty acid and cholesterol synthesis rates, and reduced fat in the liver (steatosis).
These results implicate miR-122 as a key regulator of cholesterol and fatty-acid
metabolism in the adult liver and suggest that miR-122 may be an attractive thera-
peutic target for cardiovascular and metabolic diseases.
miRNAs as Therapeutic Targets for Cardiovascular Diseases
In the search for novel molecular entities as therapeutic targets for cardiovascular
diseases, miRNAs could constitute a major breakthrough because both miRNAs
and their regulatory targets are potentially druggable. Druggability of miRNAs will
imply development of cell-permeable small molecules specifically regulating
cardiovascular miRNAs, either mimicking or antagonizing miRNAs with hope-
fully subsequent normalization of gene networks. In view of the polygenic nature
of a number of diseases, use of a single molecule to modulate a cluster of patho-
genic genes (generally encoding proteins with related functions), appears to be an
excellent idea. However, in view of the existence of several hundred miRNAs, the
major challenge will be the selection of the miRNA candidates for therapeutic
manipulation.
Safety issues should also be considered because some miRNAs expressed in
cardiovascular tissues may also be expressed in other tissues. Moreover, a single
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