Heart Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 279

regeneration of cardiomyocytes. Cardiomyocytes renew with about 1% annual
turnover at 25 years old that gradually decays down to 0.45% at 75 years old [ 502 ].
Myocardin (Myocd) is a potent transcriptional coactivator of serum response
factor expressed exclusively in cardiac and smooth myocytes during postnatal
development. It regulates maintenance and adaptation of the heart, especially
cardiomyocyte structure and organization of intercalated discs and sarcom-
eres [ 503 ]. Myocardin links to serum response factor to synergistically activate gene
transcription for heart adaptive response to growth factors and hemodynamic stress.
Myocardin-regulated

genes encode cardiac cytoskeletal and myofibrillar

structural proteins, such as cardiac α -actin-1 (ACTC gene), α -actinin-2 (ACTN2

gene), cardiac myosin heavy chain-7 (i.e., slow isoform MHC; MYH7 gene),

desmin (DES gene), dystrophin (DMD gene), and tropomyosin-1 (tropomyosin-

β

α

chain; TPM1 gene).
Growth factors activate extracellular signal-regulated kinases ERK1 and ERK2.
The latter, in turn, phosphorylate myocardin isoform-B (Ser812, Ser859, Ser866,
and Thr893) [ 504 ].
The synthesis of protein Ser/Thr kinase PIM1 in the myocardium decreases
during postnatal development, but re-emerges after acute injury. Cardioprotection
associated with PKB activation induces PIM1 expression (downstream from PKB)
to impede cardiomyocyte apoptosis and enhance calcium dynamics [ 505 ].

6.1.8 Regulators

Cardiac specification requires a permissive environment. Anterior endoderm
adjacent to the heart-forming region, the anterior mesoderm, provokes and
maintains cardiogenic fate. This endoderm region secretes many messengers, such
as fibroblast growth factors, activins and bone morphogenetic protein BMP2 of the
TGF

superfamily, and insulin-like growth factor-2 that promote cell survival and
proliferation of cardiogenic cells and differentiating myocytes [ 483 ].
Cardiogenesis relies on few recycled functional modules that integrate into
protein networks according to a given spatiotemporal control to drive the stages
of organ development [ 506 ]. Complicated organ are thus built using simple building
blocks that coordinate morphogenesis.

β

6.1.8.1 Transcription Factors

Homeobox gene products, such as members of the homeobox HOX and NK2
families, as well as transcription factors of the helix-loop-helix superfamily such as
the myogenic genes (e.g., myogenin [Myog], or myogenic factor-4, myogenic dif-
ferentiation factor-1 [MyoD or MyoD1], myogenic factor-5 [MyF5], and myogenic
regulatory factor MRF4) participate in cell lineage commitment.