Biomedical Engineering Reference
In-Depth Information
6.1.8.6
Matrix Proteoglycans
Perlecan is a heparan sulfate proteoglycan in basement membranes that binds to
integrins and dystroglycan, interacts with extracellular matrix components, and
recruits growth factors and modulates their activity. Perlecan stabilizes the heart
wall during cardiogenesis as well as in adults after injury. Basement membranes
that lack perlecan deteriorate and lead to cell detachment in the ventricle and outflow
tract and blood leakage into the pericardial cavity [
525
].
At the onset of cardiogenesis, perlecan serves as an adhesive substrate for
cardiomyocytes with laminin and collagen-4 and maintains mechanically stressed
basement membrane surrounding cardiomyocytes to ensure mechanical stability.
At later stages, heart stability is achieved by formation and maturation of intercel-
lular contacts such as intercalated discs composed of desmosomes and adherens
junctions that are composed of
-catenin
25
and cadherin, respectively.
γ
6.1.8.7
MicroRNAs
Cardiogenesis depends on the spatiotemporal expression of microRNAs.
MicroRNAs control the expression of messenger RNAs that are translated into
regulators of cardiogenesis, propagation of electrochemical waves, and myocardium
hypertrophy and contractility (Table
6.4
).
MicroRNAs commonly bind to mRNAs and inhibit mRNA translation with
or without mRNA cleavage. The most abundant microRNAs in the myocar-
dium are miR1, miR133, miR126-3p, miR30c, miR26a, and the (lethal) Let7
class [
526
]. MicroRNAs MiR1, miR133, and miR208 are specific to striated
myocytes. The microRNA-1 set comprises 2 transcripts miR1-1 and miR1-2 that
are encoded by distinct genes. The miR133 set includes miR133a-1, miR133a-2,
and miR133b. MicroRNA-208 is encoded by an intron in the MYH6 (
MHC) gene.
Muscular microRNAs, such as miR1 and miR133, are mainly controlled by
myogenic transcription factors. MicroRNA-1 targets histone deacetylase HDAC4,
a transcriptional repressor of muscle gene expression. It also controls cardiogenesis
in mice, as it regulates cardiac transcription factor bHLHa26 [
531
]. MicroRNA-133
enhances myoblast proliferation by repressing serum response factor that acts in
sarcomere organization.
Serum response factor is controlled by other regulators, such as GATA4, NKx2-5,
and myocardin, as well as microRNAs, such as miR1-1, miR1-2, miR21, miR133,
miR206, miR214 [
531
]. Conversely, serum response factor regulates microRNAs
such as miR1-1, miR1-2, miR133, and miR129 in cardiomyocytes.
26
α
25
A.k.a. plakoglobin.
26
Regulator of muscular development MEF2, in cooperation with MyoD, activates transcription of
miR1-2 and miR133a-1 in skeletal myocytes.
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