Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 246

5.8.2.5 Receptor Protein Tyrosine Kinases

The receptor protein Tyr kinase human epidermal growth factor receptor HER2 links
to HER3 or HER4 and binds neuregulin, thereby hampering cardiomyocyte growth
(Fig. 5.14 ).
Exercise activates the IGF1-PI3K c1α -PKB pathway. Kinases PKB activated
by IGF1R and PI3K c1α promote growth and survival of cardiomyocytes. On the
other hand, PKB stimulated by GPCR (ET1R) and PI3K c1γ induces maladaptive

hypertrophy.
The receptor Tyr kinases of insulin-like growth factor-1 74 and fibroblast growth
factor, receptor Ser/Thr kinases of transforming growth factor- , and cardiotrophin-

1, as well as G-protein-coupled receptors and stresses, stimulate the MAPK
cascades.
Receptor HER2 is involved in cardiogenesis. It acts as a survival factor in
adult myocardium. Inhibition of HER2 causes mitochondrial dysfunction in car-
diomyocytes. Certain HER2 inhibitors (herceptin) favor cardiomyopathy. Other
HER2 inhibitors (GW2974) activate AMP-activated protein kinase and protect
the cardiomyocyte against TNF

β

-induced death [ 417 ]. Inhibition of HER2 blocks
HER3 transactivation by HER2, increasing intracellular calcium level.

α

5.8.2.6 PI3K-PKB Axis

Activated PI3K leads to the sarcolemmal recruitment of protein kinase-B and
phosphoinositide-dependent kinase-1 that phosphorylates (activates) protein

kinase-B.
Isoform PI3K c1α is strongly implicated in exercise-induced hypertrophy
(Fig. 5.15 )[ 418 ]. Moreover, elevated PI3K c1α activity improves cardiac function
and limits fibrosis; hence, it attenuates maladaptive cardiac hypertrophy in mouse
model

of dilated cardiomyopathy subjected to pressure overload caused by

ascending aorta constriction.
Glycogen synthase kinase GSK3 , targeted by protein kinase-B, represses

cardiac hypertrophy transcription effectors. However, protein kinase-B also ac-
tivates the Ser/Thr protein kinase target of rapamycin, thereby favoring cardiac
hypertrophy.
In addition, growth and differentiation factor GDF8 (or myostatin) precludes
striated myocyte hypertrophy, as it prevents P38MAPK and PKB phosphorylation,
but does not suppress PKB phosphorylation induced by IGF1 [ 419 ]. Furthermore,
PI3K c1α impedes signaling from G-protein-coupled receptor, PI3K c1γ ,andPKBin
isolated cardiomyocytes (Fig. 5.15 ). PI3K c1α hinders ERK1 and ERK2 activation,
acting upstream from ERK1 and ERK2 kinases.

β

74 Binding of IGF1 to its receptor activates PI3K c1α that converts plasmalemmal phosphatidylino-
sitol (4,5)-bisphosphate to phosphatidylinositol (3,4,5)-trisphosphate, hence activating signaling.