Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 250

5.8.2.13 Follistatins

The balance between members of the TGF , activins, BMPs,

and GDFs; Vol. 2 - Chap. 3. Growth Factors) and their inhibitors (follistatins,
inhibins, and nodal) regulates various physiological and pathological processes
(e.g., cardiac fibrosis, myocardial ischemia-reperfusion injury, pressure-overload-
induced cardiac hypertrophy, and heart failure). Proteins of the follistatin family
may bind to and modify the function of members of the TGF

β superfamily (TGF β

superfamily (activin-
A, BMP2, and GDF8) that can either prevent or promote growth by signaling
via SMAD transcriptional regulators. The SMAD proteins (SMAD2-SMAD4) are
implicated in the regulation of cardiac hypertrophy. In particular, Follistatin-like
protein FStL3 binds to activin-A and intervenes the heart's response to ischemia
and pressure overload. On the other hand, follistatin-like protein FStL1 can rapidly
activate intracellular pathways in cardiovascular cells in the absence of TGF

β

β

family proteins [ 427 ].
Follistatin-like protein FStL1, an extracellular glycoprotein, protects the heart
from ischemia-reperfusion injury. The FSTL1 transcript is produced in cardiomy-
ocytes as well as vascular endothelial and smooth muscle cells [ 427 ]. Its expression
is upregulated in the myocardium, mainly in cardiomyocytes, in response to pressure
overload. The secreted cardiokine FStL1 does not contribute to heart growth in
normal conditions. However, it precludes cardiac growth in pressure overload-
induced hypertrophy [ 427 ]. Protein FStL1 promotes a rapid AMPK phosphorylation
(activation). 77 Activated AMPK phosphorylates NOS3 (Ser1179); NO impedes
maladaptive cardiac hypertrophy and favors angiogenesis.
Activin-A and GDF8 impede CMC hypertrophy; their effect is antagonized by
follistatin (FSt) and cardiac follistatin-like protein FStL3. The latter, an extracel-
lular, stress-induced regulator of activin-A (which precludes SMAD2 activation),
binds to activin-A with a much higher affinity than the former. Amount of FStL3
rises in cardiomyocytes of patients with heart failure.

5.9 Cardiomyocyte Orientation

Cardiac myofibers run in the heart wall as helices around the ventricles, strengthen-
ing them. Myofiber geometry enables an efficient wall reinforcement, as they render
stiffness uniform in all directions parallel to their localization plane. Bundles of
myofibers are usually represented into sheets across the wall thickness with a given
orientation.

77 Adiponectin is another peptide regulators of cardiac AMPK kinase. Protein FStL1 may operate
via the receptor Disco-interacting protein-2 homolog-A (DIP2a).