Endothelin-1, a potent endothelium-derived
vasoconstrictor peptide, exerts a growth-promoting effect on vascular smooth muscle
cells, implicating its pathogenic role in vascular remodeling.
Endothelin-1 action is exerted by its binding to Endothelin
receptor type A (EDNRA) [1].
EDNRA belongs to the superfamily of rhodopsin-like
proteins comprising seven transmembrane-spanning regions. These proteins are involved in
intracellular signaling pathways through activation of associated guanine nucleotide
binding proteins (G-proteins). EDNRA is bound with
G-protein alpha-s,
G-protein alpha-q/11 and G-protein alpha-i
family [2], [3], [4]. The exact
G-proteins and signaling cascades are not known.
EDNRA probably activates Adenylate cyclase
via G-protein
alpha-s and, thus, enhances
intracellular concentration of Cyclic AMP
(cAMP) [2], [5], [6].
Other G-proteins, G-protein
alpha-q/11 and G-protein alpha-i family,
after ENDRA stimulation by
Endothelin-1 dissociate from complex with beta\gamma
subunits, and activate any Phospholipase C beta (PLC-beta), e.g. Phospholipase C beta 3
(PLC-beta3). PLC-beta3
hydrolyses of Phosphatidylinositol 4,5-bisphosphate
(Ptdins(4,5)P2) and the generation of Diacylglycerol
(DAG) and Inositol trisphosphate
(IP3) [7], [8], [9].
DAG and IP3 stimulate Protein
kinase C, delta and epsilon (PKC-delta and
PKC-epsilon) and mobilize intracellular Ca('2+),
respectively [10], [11], [12], [13].
PKC-delta, PKC-epsilon
and Ca2+ (via intermediate, presumably -
Calcium/calmodulin-dependent protein kinase II (CaMK II))
activate PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2))/
v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog
(c-Src) complex [11], [12].
G-protein alpha-s
and G-protein alpha-i may
activate c-Src directly [14].
Many Endothelin-1-induced cascades may be activated via
c-Src.
For example, c-Src phosphorylates SHC (Src homology 2
domain containing) transforming protein 1 (Shc). It leads to
activation of Growth factor receptor-bound protein 2 (Grb2)/ Son of sevenless homologs (Sos) complex.
Sos catalyzes conversion of v-Ha-ras Harvey rat sarcoma
viral oncogene homolog (H-Ras) from GDP- to GTP-form.
H-Ras-GTP is then binds to and activates v-raf-1 murine
leukemia viral oncogene homolog 1 (c-Raf-1)/
Mitogen-activated protein kinase kinases 1 and 2
(MEK1(MAP2K1) and MEK2(MAP2K2))/ Mitogen activated protein kinases 3 and 1 (ERK1/2) [11], [12].
Endothelin-1/
EDNRA-dependent ERK1/2 may stimulate any
translation factor (e.g., ELK1, member of ETS oncogene family
(Elk-1)), which, in turn, activates transcription of cardiac
hypertrophic protein Natriuretic peptide precursor B (BNP)
[15]. In addition, ERK1/2 activation leads to
cell proliferation [11], [12].
On the other hand, Endothelin-1/
EDNRA-activated c-Src may
phosphorylate guanine-nucleotide exchange factor FERM,
RhoGEF and pleckstrin domain protein 2 (FARP2).
FARP2 activates Cell division cycle 42
(CDC42)/ Mitogen-activated protein kinase kinase kinase 1
(MEKK1(MAP3K1))/ Mitogen-activated protein kinase kinase 4
(MEK4(MAP2K4))/ Mitogen-activated protein kinases 8-10
(JNK(MAPK8-10)) cascade. This pathway leads to inhibition of
cell motility [16].
An unknown c-Src-activated guanine-nucleotide exchange
factor (e.g., FARP2) stimulates
Ras-related C3 botulinum toxin substrate 1
(Rac1)/ phosphatidylinositol 3 kinase
(PI3K)/ v-akt murine thymoma viral oncogene homolog 1
(AKT(PKB)). Activation of AKT(PKB)
leads to matrix contraction [17]. In addition, activation of
the PI3K/ AKT(PKB) inhibits
Glycogen synthase kinase 3 beta (GSK-3beta) by
phosphorylation, which, in turn, leads to stabilization of the active soluble
form of Catenin (cadherin-associated protein), beta
1 (Beta-catenin). Beta-catenin
activates Transcription factor 7-like 2 (TCF-4), which
activates transcription of Cyclin D1. Moreover,
Beta-catenin/ TCF-4 enhances
Endothelin-1 promoter activity in a reciprocal manner.
Activation of the Beta-catenin/ TCF-4 cascade by
Endothelin-1 results in the proliferation and inhibits
apoptosis [18].
Moreover, c-Src may activate Mitogen-activated protein
kinase kinase kinase 4 MEKK4(MAP3K4)/ Mitogen-activated
protein kinase kinase 6 (MEK6(MAP2K6))/
Mitogen-activated protein kinases 14
(p38alpha(MAPK14)) cascade {PMID:
9679149}, [19] via some small GTP binding proteins (e.g.,
CDC42). p38alpha(MAPK14)
stimulate by phosphorylation GATA binding protein 4
(GATA-4), and Elk-1 which in
turn activates transcription of cardiac hypertrophic protein
BNP [15], [20].