Transforming growth factor β
The motor of EndMT is the transforming growth factor β (TGF-β) pathway,
which includes multipotent cytokines that are important modulators of
cell growth, inflammation, matrix synthesis and apoptosis. TGF-β
regulates as well the change of VICs from quiescent to active and is
able to differentiate mesenchymal cells into myofibroblasts and to
regulate multiple aspects of the myofibroblast phenotype.
Beyond the TGF-β superfamily, there are other mediators of EndMT.
Several stimuli or pathways, converging with TGF-β signaling, as shear
stress8, glucose9,
endothelin-110 and angiotensin II11,
can stimulate EndMT (fig. 6). Others, as fibroblast growth factors and
Wnt/β-catenin signaling inhibit with different mechanisms EndMT. Other
factors, as non-coding RNAs, can degrade the messangerRNA, inhibiting
its translation into protein12. This mechanism can
favor or inhibits EndMT.
TGF-β is secreted as a large latent complex, unable to associate with
its receptors. The extracellular concentration of TGF-β activity is
primarily regulated by conversion of latent TGF-β to active TGF-β;
activation of only a small fraction of this latent TGF-β generates
maximal cellular response13. Latent TGF-β is
considered to be a molecular sensor that responds to specific signals by
releasing TGF-β. These signals are often associated with phenomena such
as angiogenesis, wound repair, inflammation and, perhaps, cell growth.
Other modes of activation have been proposed, including
integrin-mediated release, which can result from mechanical force
transduction14.
Activated TGF-β mediates its effects by binding specific transmembrane
receptors at the cell-membrane15 that phosphorylate
specific transcription factors which translocate to the nucleus, where
they regulate the transcription of specific target genes, which induce
myofibroblast activation and matrix deposition. This mechanism
facilitates tissue remodeling and wound healing but also plays a
pathological role in fibrotic disease. After completion of remodeling
activities, myofibroblasts are eliminated by
apoptosis16; however, when the myofibroblast life
cycle is not regulated properly, myofibroblasts persist with continued
force generation and ECM production, resulting in pathological fibrosis,
scarring, and fibrocontractile disease17. (fig. 7).
The renin-angiotensin system is markedly activated in response to acute
myocardial infarction (AMI) and directly induces cellular responses in
both cardiomyocytes and interstitial cells18.
Angiotensin II stimulates fibroblast proliferation and expression of
proteins18, through ECM interactions involving the
Angiotensin Type 1 (AT1) receptor. Extensive evidence suggests a direct
functional association between the renin-angiotensin system and the
TGF-β pathway, indicating that TGF-β1 acts downstream of Angiotensin II
(fig. 6)18. In addition, angiotensin II increases VICs
responsiveness to the fibrogenic actions of TGF-β19.