Heart Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 283

Cardiomyocytes in the adult myocardium produce HER2 and HER4 recep-
tor protein Tyr kinases. Neuregulin-1 binds to HER4 with high affinity; HER4
dimerizes preferentially with HER2 receptor. 18 Receptor HER2 of the HER2-
HER4 heterodimer acts as a non-autonomous amplifier. In the heart, neuregulin-1
primes [ 514 ]: (1) the Src-FAK, (2) SHCa-MAPK, and (3) PI3K-PKB pathway.
Neuregulin-1 contributes to cardiomyocyte differentiation from stem and
progenitor cells, migration, and proliferation during cardiogenesis as well as
during the postnatal myocardial development that involves the population of
mononucleated

cardiomyocytes and cardiac regeneration in damaged adult

hearts [ 514 ]. 19

TGF “

Transforming growth factor- β receptor T β R3, a coreceptor for members of the

TGF superfamily, resides in the heart fields [ 483 ]. It acts as a permissive factor in

cardiogenesis. Coreceptor TGFBR3 is involved in Nodal signal transduction. Nodal
signaling contributes to endoderm formation [ 483 ].
Member of the tumor-necrosis factor superfamily TNFSF12 regulates
proliferation of several cell types, among which are cardiomyocytes. This
type-2 transmembrane glycoprotein is processed into a soluble cytokine. In
neonatal cardiomyocytes, TNFSF12 upregulates the expression of activators of
cardiomyocyte proliferation, such as nuclear marker of cellular proliferation Ki67,
mitotic marker phosphohistone-3 (H3 P ), cyclin-D2, and Aurora-B kinase, as well
as represses that of cyclin-dependent kinase inhibitor CKI1b [ 516 ]. Cytokine
TNFSF12 targets TNFRSF12a receptor that signals via activated extracellular
signal-regulated kinases and phosphatidylinositol 3-kinase as well as inhibition
of glycogen synthase kinase-3

β

. In adult cardiomyocytes, induction of cell cycle
re-entry requires TNFRSF12a re-expression.

β

6.1.8.4 Morphogens

The NKX2-5 promoter contains several SMAD binding sites. Bone morphogenetic
protein BMP2 can elicit the expression of myocardial lineage markers. On the other
hand, noggin that binds to and inhibits BMPs (as it precludes TGF β family ligands

18 Receptor HER4 also binds NRg2 to NRg4, HBEGF, and epiregulin. Receptor HER4 has multiple
isoforms generated by alternative splicing [ 515 ]. Alternatively spliced variants can be categorized
into juxtamembrane domain variant-A and -B (HER4 JMa and HER4 JMb ) and cytoplasmic tail
variant-1 and -2. Variant HER4 Cyt1 is produced predominantly in the heart and breast. Variant
HER4 Cyt2 ), synthesized mainly in the nervous system and kidney, lacks a binding site for P85 PI3K
subunit, thus being unable to stimulate PI3K, but remaining functional, as it binds neuregulin-1.
19 Daughters of cardiomyocytes needs to have electromechanical connections to cooperate electri-
cally and mechanically with the surrounding myocardium.