Heart Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 299

All 3 natriuretic peptides trigger the production of cGMP, an inhibitor of
cardiomyocyte hypertrophy. Receptor NP 3 is involved in the regulation of fibroblast
proliferation. 45 On the other hand, ANP impedes the activity of ERK and P38MAPK
in smooth myocytes in response to angiotensin-2 [ 571 ].
Myocardial and coronary development is coupled via bone morphogenetic
proteins as well as fibroblast (FGF) and vascular endothelial (VEGFa) growth
factors [ 493 ]. The transcription factor GATA4 regulates cardiac gene expression,
thereby modulating cardiomyocyte differentiation and adaptation in adult hearts.
In cardiomyocytes, ERK1, ERK2, and P38MAPK kinases phosphorylate (activate)
GATA4 transcription factor that promotes myocyte survival and hypertrophy. Factor
GATA4 regulates the transcription of numerous peptides synthesized in cardiomy-
ocytes, such as ANP, BNP, -myosin (MyH7) heavy chains,

and endothelin-1 that causes cardiomyocyte hypertrophy [ 572 ]. Cardiac lineage-
promoting GATA4 factor produced by cardiomyocytes stimulates angiogenic factor
VEGFa that targets endothelial cells [ 573 ].
Both embryonic and adult cardiofibroblasts produce GATA4 factor. In cocultures
of embryonic cardiac fibroblasts and myocytes, the former provoke proliferation of
the latter [ 574 ]. Endothelin-1 serves as an autocrine stimulator of fibroblast prolifer-
ation. In cardiofibroblasts, ANP produced in neighboring cardiomyocytes prevents
the synthesis of endothelin-1, as it suppresses GATA4-dependent transcriptional
activity [ 571 ].

α -(MyH6)and β

6.2.1.4 Effects of Angiotensin-2

Angiotensin-2 is involved in matrix constituent accumulation, especially during
cardiac remodeling after long-term exposure of pressure overload. Angiotensin-2
promotes the synthesis of periostin, a matrix protein and regulator of cardiac fibro-
sis [ 575 ]. 46 Angiotensin-2 provokes activation of the RasGRP1-Ras-P38MAPK-
CREB pathway. cAMP response element-binding protein responds to different
stimuli and mediates the fibrotic response. In addition, ERK1 and ERK2 participate
in angiotensin-2-induced periostin expression via the TGF β 1-SMAD2/3 axis.

45 Second messenger cGMP inhibits TGF

1-induced phosphorylation of SMAD3, hence preclud-
ing myofibroblast transformation and proliferation as well as synthesis of extracellular matrix
proteins.
46 Periostin is secreted primarily by osteoblasts and fibroblasts. It is produced in the bone and, to
a lesser extent, in the lung, kidney, and heart valves under normal conditions. However, periostin
expression rises in heart failure.

β