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Klinisk Biokemi i Norden
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Fortsat fra side 38)
cancer and other disease states, miRNAs released by
tumor tissue could represent an even more powerful
new class of minimally invasive, blood-based bio-
markers for cancer detection. Accordingly, it raises
the possibility of using circulating miRNAs as novel
markers of different diseases given the close associa-
tion between specific miRNA profiles (quality/quan-
tity) and several disease states (19). Recently, highly
stable miRNAs were discovered in serum and plasma
samples (20), partly present and protected by vesicles
of endocytic origin, the exosomes (21). miRNAs may
emerge as a new class of blood-based biomarkers with
great potential, representing a new approach to diag-
nostic screening of blood.
MicroRNA in cardiac disease
Early work focused on miRNA profiles in the myo-
cardium
The discovery of miRNA function and regulation was
swiftly adopted by the cardiology community. The
potential of one miRNA (miR) to regulate several
mRNAs, and thereby also regulate a network of down-
stream protein targets, was intriguing and considered
a future therapeutic target (22). The initial focus was
on miRNA expression during cardiac pathophysiol-
ogy, and with a special focus on the regulation of
miRNA in the myocardium in heart failure (HF). This
work was mainly carried out in experimental animal
models, although some researchers also presented
data from human cardiac tissue. To identify miRs that
were altered during cardiac disease, miRNA microar-
ray profiles in animals with cardiac disease (coronary
artery ligation, transverse aortic banding, genetically
induced cardiac disease, etc) were compared to the
profile of healthy (sham-operated) animals. However,
as several different microarray platforms, species, time
point of tissue sampling, and experimental models
were used a number of different miR profiles were all
proposed as the “miRNA signature of cardiac disease”
(23).
Some of these results are presented in Figure 3,
which is a non-exclusive list of miRNAs altered with
cardiac pathophysiology.
The therapeutic potential of miRNA based interven-
tion
The advent of genetically modified animals has been
important for examining effects of individual miRs.
With the use of gain- and loss-of-function studies
one can examine the effect on animal phenotype by
an isolated miR overexpression or deletion. Growth
of cardiomyocytes (hypertrophy) and remodeling of
the myocardium (alterations in extracellular matrix/
fibrosis) are two principal processes in HF, and the
effect of manipulating miRs to alter these processes
has been studied extensively. Consistent with the model
that miRNA regulate several downstream targets, strik-
ing alterations in animal function and phenotype have
been reported by deleting or enhancing single miRs
(
see ref. 24 for review). Still, recent inconsistency in
the data for miR-21 (25,26) has demonstrated a need
A.
Figure 2
Steroid hormone
Hsp
Hsp
HRE
Target gene
R
B.
Figure 2
Hormone
HRE
RxR
Target gene
RxR
Target gene
HRE
Figure 2. miRNAs: Key regu-
lators of gene expression with
great flexibility. Interaction
of miRNA and complemen-
tary binding sites on target
messenger RNA (mRNA)
initiates post-transcriptional
gene regulation and inhibi-
tion of the protein synthe-
sis of the target mRNA.
Functional miRNA activ-
ity does not require perfect
sequence homology between
miRNA and target mRNA,
and opens for a great binding
flexibility and a broad regu-
latory capacity.
