Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 736

11.8.1 Myocardium Remodeling

Acute myocardial infarction leads to necrosis of cardiomyocytes and other cells. The
inflammatory response triggers the migration of platelets, neutrophils, macrophages,
monocytes, and other inflammatory mediators to the infarction site, where matrix
metallopeptidases (MMP) degrade components of the extracellular matrix. Regions
of fibrosis are formed as collagen is deposited. The fibrotic areas of infarctions do
not have the contractile function, without regional myocyte regeneration, appropri-
ate matrix formation, and angiogenesis.
The heart contains very rare cardioblasts (with a decreasing number with age) for
self-regeneration, especially after a heart attack [ 1478 ]. These cardioblasts are sus-
ceptible to divide and mature after birth. Unlike stem cells, cardiac progenitor cells
undergo a finite number of divisions and become fully specialized cardiomyocytes.
Cardiomyocyte proliferation from cardiomyocytes, resident stem cells, endothe-
lial cells, fibroblasts, or migrated hematopoietic stem cells in areas adjacent to the
infarcted zone can be a regeneration source.
Adequate input of growth factors is necessary to stimulate the myocardial
regeneration with needed angiogenesis and matrix formation to avoid maladaptive
remodeling of the myocardium.
Embryonic stem cells lead to 2 types of cardiovascular progenitors that express
VEGFR2 [ 546 ]. The first type of VEGFR2

cells act as hemangioblasts ,giving
birth to hematopoietic and endothelial cells. The second type gives rise to car-
diomyocytes and endothelial and smooth muscle cells. The pathways (Wnt, TGF

+

1,
BMPs, and their antagonists, FGFs, etc.), which regulate cardiogenesis, may be used
for stem cell-based cardiac repair.
Granulocyte colony-stimulating factor (CSF3) participates in heart regeneration
after myocardial infarction. It activates the JaK-STAT pathway in cardiomyocytes,
phosphorylating STAT3 and JaK2 [ 1479 ]. It has an anti-apoptotic effect, with
increased levels of the anti-apoptotic BCL2 and BCLxL proteins. However, CSF3
stimulates angiogenesis, but not the proliferation of cardiomyocytes.
Lipopolysaccharides

β

and postischemic reperfusion activate myocardial

P38MAPK and nuclear factor- B that lead to TNF production by cardiomy-

ocytes [ 1480 ]. Tumor-necrosis factor depresses myocardial function by NO- and
sphingosine-dependent mechanisms. It can also cause cardiomyocyte apoptosis.
Tumor-necrosis factors and lipopolysaccharides induce distinct biological
responses, although they use the same signaling pathway with the effector nuclear
factor-

κ

B, via TNF receptor-1 and Toll-like receptor-4, respectively. Positive and
negative feedbacks determine the timing of transcription factor activity and control
the expression of genes mediated by the same transcription factor [ 1481 , 1482 ].
TNF-dependent activation of IKK reaches its peak between 5 and 15 minutes and
then shows oscillatory behavior if the stimulus is continued, whereas LPS-mediated
signaling induces a slower biphasic IKK response (a small initial followed by a
larger increase and slow attenuation).

κ