Biomedical Engineering Reference
In-Depth Information
Calcium ions then stimulate the PP3-NFAT pathway and inactivate the
CamK-HDAC axis. Activated proteins of the Gq/11 set stimulate MAPK
modules. These biochemical cascades mediate cardiomyocyte growth and possible
hypertrophy.
73
5.8.2.3
Angiotensin-2
Angiotensin-2 causes cardiomyocyte hypertrophy via the nuclear factor of activated
T cells, after activating phospholipase-C that produces inositol trisphosphate and
diacylglycerol (Fig.
5.13
). The former generates calcium influx via IP
3
R, emptying
the intracellular calcium stores; the latter enhances the frequency of calcium
oscillations triggered by membrane depolarization via the activation of store-
operated diacylglycerol-sensitive TRPC channels, especially TRPC3 and TRPC6
channels [
414
]. The resulting Na
+
and Ca
2
+
entries in the cytosol change sarcolem-
mal potential and subsequently stimulate Ca
V
1.2 channels.
cADP
Ribose is a Ca
2
+
-mobilizing second messenger produced from NAD
+
by
ADP
ribosyl cyclase.
ADP
ribosyl cyclase is activated by angiotensin-2 (that promotes
cardiomyocyte hypertrophy) and subsequent, sequential stimulation of Src, phos-
phatidylinositol 3-kinase, protein kinase-B, phospholipase-C
1, and IP
3
-mediated
Ca
2
+
[
415
]. Angiotensin-2 generates a biphasic intracellular Ca
2
+
concentration
increase with a rapid transient Ca
2
+
elevation via inositol trisphosphate receptor and
sustained Ca
2
+
influx mediated by
ADP
ribose through activated Ca
V
1.2 channels and
ryanodine receptors.
γ
5.8.2.4
GPCR-G-Protein Signaling
Cardiomyocyte stretch acts on the angiotensin-2 type-1 receptor (AT
1
) that links
to Janus kinase-2, hence translocating G-proteins into the cytosol, activating the
extracellular signal-regulated kinase, and leading to hypertrophy.
α
1-Adrenergic receptors coupled to G
α
q
play a role in cardiac hypertrophy.
Subunits
of
the
G
α
q
/
11
subclass
of
guanine
nucleotide-binding
protein
(G
. Activated
phospholipase-C produces diacylglycerol that binds to and activates protein kinase-
C as well as inositol (1,4,5)-trisphosphate. The latter binds to intracellular IP
3
receptor, leading to the release of internal Ca
2
+
stores. Diacylglycerol also augments
the concentration of cytosolic free calcium in cardiomyocytes. Calcium liberated
from its intracellular stores regulates PP3 that controls NFAT transcription factor.
Subunit G
protein,
i.e.,
G
αβγ
trimer)
is
coupled
to
phospholipase-C
β
α
q
also stimulates the mitogen-activated protein kinase modules and
PKC-PKD pathway.
73
Physiological cardiac hypertrophy over a limited time preserves the ventricular function.
Pathological hypertrophy responds to sustained long-term pressure overload.
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