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by up-regulating cardioprotective proteins including HO-1 and
COX-2 and the anti-apoptotic proteins Bcl-x
L
, Mcl-1, c-FLIP
L
,
and c-FLIP
S
(
111
). Interestingly, we have previously also shown
that Hyper-IL-6 trans-signaling through STAT3 encounters a tis-
sue protective effect in the kidney (
66
). These observations further
support previous reports stating that the conditional cardiomyocyte-
specific STAT3 KO mice were susceptible to cardiac injury caused
by myocardial ischemia. Cardiomyocyte-specific STAT3-KO mice
were also more prone to age-related heart failure. The cardiopro-
tective effect of STAT3 is also induced through the SDF/CXCR4
signaling in an ischemic/reperfusion model (
112
). (4) Mice with a
cardiomyocyte-restricted deletion of gp130 develop massive car-
diomyocyte apoptosis and dilated cardiomyopathy when subjected
to biomechanical stress (
113
). These same mice are susceptible to
myocardial ischemia/reperfusion injury and infarction. This was
shown by increased cardiomyocyte apoptosis, larger infarct sizes,
reduced cardiac function and a reduced long-term survival after
infarction (
114
). Interestingly, it was also reported that gp130 sig-
naling in the myocardium is essential to prevent transition to con-
gestive failure (
113
). (5) Diabetes mellitus is a major risk factor for
coronary heart disease. It has been recently shown by the group of
Jonathan Axelrod that STAT3 signaling is attenuated in the diabetic
rat at a preconditioning state (
115
). This effect explains the cardio-
myopathy associated with diabetes mellitus. This phenomenon
could explain the abrogation of cardioprotection of precondition-
ing. (6) AKT is activated upon stimulation of gp130 in addition to
STAT3 phosphorylation. In a number of studies it was also shown
that AKT activation has protective properties and possibly also a
regenerative effect on the heart upon acute injury (
116, 117
).
Interestingly, these studies show that decreasing PTEN levels by
microRNA-1 allowed the activation of AKT and prevented apop-
tosis of cardiomyocytes encountering a protective effect. The pro-
tective effect of the Granulocyte colony-stimulating factor (G-CSF)
is also mediated through AKT activation (
118
).
9
Nerve Growth and Regeneration: The Role of IL-6-gp130
Axonal regeneration is a process dependent on SOCS3 depletion.
SOCS3 is a feedback inhibitor of gp130 signaling. Upon IL-6
interaction with gp130 and the induction of signaling, SOCS3 is
activated and suppressed the gp130 downstream effects, resulting
in the cessation of its activation. A prolonged and sustained activa-
tion of IL-6 signaling could overcome SOCS3 effects and enable a
prolonged AKT activation. Interestingly, both, PTEN suppression,
leading to AKT activation and SOCS3 inhibition are two essential
components for axonal regeneration (
119, 120
). However,
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