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Have you read ? Best of the Best: Basic Research
by Javier Angulo
Javier angulo, Phd
Associate Editor
Departamento de Investigación
IRYCIS Hospital Universitario
Ramón y Cajal
Madrid, Spain
javier.angulo@hrc.esPeyronie’s disease – Inhibiting the TGF-
ß1
pathway in fibroblasts
Effect of Smad7 gene overexpression on
TGF-ß1-induced profibrotic responses in
fibroblasts derived from Peyronie’s plaque.
Choi MJ, Song KM, Park JM, Kwon MH, Kwon
KD, Park SH, Ryu DS, Ryu JK, Suh JK.
Asian J Androl – doi: 10.4103/1008-628X.
142130 2014 Dec 5 [Epub ahead of print].
Although aetiology of Peyronie’s disease (PD) is
not completely elucidated, it seems to involve an
inflammatory process in tunica albuginea. In this
sense, overexpression of profibrotic cytokines
contributes to the development of the plaque.
The cytokine most consistently associated with
the pathogenesis of PD is transforming growth
factor-ß1 (TGF-ß1). In fact, injection of TGF-ß1
in the penis of the rat causes a pathological
process resembling some characteristics of
PD in humans while expression and activity of
TGF-ß1 and its downstream effectors, Smad2
and Smad3 is increased in human PD plaques
and fibroblasts derived from human PD plaques.
Although some members of the family of proteins
Smad are key participants in fibrotic process
induced by TGF-ß1 activation, other members
have inhibitory activity on this process. This is
the case for Smad7 which has been shown to
antagonize TGF-ß1-induced alterations in models
of fibrotic pathologies.
The work by Choi and collaborators aimed to
evaluate the overexpression of Smad7 in hu-
man fibroblasts derived from PD plaque as a
strategy to overcome the pro-fibrotic phenotype
induced by exposure of these cells to TGF-ß1.
They isolated and cultured fibroblast obtained
from surgical specimens of human PD plaque
tissues. The cells were transfected with a vector
including the Smad7 gene or by the vector alone.
The changes in phenotype caused by exposure
to TGF-ß1 were evaluated in the two types of
transfected cells.
The increased production of extracelullar matrix
proteins, collagen I and collagen IV induced by
TGF-ß1 in human PD fibroblasts was markedly
inhibited by overexpression of Smad7 protein.
A key point in the generation of fibrotic events
is the transformation of fibroblast into myofi-
broblasts, which are thought to be responsible
for fibrotic response. The phenotypic change
identifying this transformation is the expression
of the contractile protein
α
-actin. TGF-ß1 expo-
sure induced expression of
α
-actin in PD fibro-
blasts, consistent with the known involvement
of TGF-ß1 in transformation into myofibroblast
phenotype. Overexpression of Smad7 reduced
the expression of
α
-actin, suggesting the in-
hibition of myofibroblast appearance among
PD fibroblast culture. Smad7 upregulation also
caused a reduced expression of cyclin D1, a
positive cell cycle regulator and an increase in
apoptosis of PD fibroblasts. The inhibitory effects
of Smad7 are likely mediated by the interference
with downstream effectors of TGF-ß1 since its
overexpression inhibited phosphorylation (acti-
vation) and nuclear localization of Smad2 and
Smad3 induced by TGF-ß1. Finally, Smad7
overexpression stimulated the expression of poly
(ADP-ribose) polymerase-1 (PARP-1) that termi-
nates transcription mediated by Smad proteins.
The authors conclude that the increased expres-
sion of Smad counteracts the extracellular matrix
deposition induced by activation of Smad2/3 that
drive the myofibroblastic differentiation triggered
by TGF-ß1. These inhibitory effects on fibrotic
phenotype of PD fibroblasts would potentially
combat the development and progression of
PD plaque. However, although differentiation of
tunical fibroblasts into myofibroblasts has been
shown as a high throughput method for screen-
ing potential candidate drugs for the treatment
of PD, the
validation of this target (Smad7)
in
in vivo models of PD seems to be required
. In
this sense, cell transfection with Smad7 gene ap-
pears as a way of therapy that presents practical
difficulties. In this context, some pharmacological
approaches (sesamin, abnormal savda munziq,
resveratrol) have been shown to produce anti-
fibrotic effects by up-regulating Smad7 expres-
sion. This could be considered for evaluation in
PD. On the other hand, the local
administration
should also be considered since Smad7 over-
expression is related to pathological situa-
tions like Crohn’s disease
(N Engl J Med 2015,
372:1104-12). An additional question to answer
is if overexpression of
Smad7 would target only
incipient stages of PD or could be beneficial
in stable plaques
, maybe in combination with
collagenase administration.
Diabetic ED – Bypassing NO deficiency
Beneficial effect of the soluble guanylyl cy-
clase stimulator BAy-41-2272 on impaired
penile erection in db/db-/- Type II diabetic
and obese mice.
Nunes KP, Teixeira CE, Priviero FB, Toque HA,
Webb CB.
J Pharmacol Exp Ther 2015, 353: 330-9.
Diabetes is not only associated with a threefold
increase in the risk of suffering ED but also to a
poorer response to conventional oral treatment
for ED (i.e. PDE-5 inhibitors). Penile arteries and
corpus cavernosum from diabetic men display
an exacerbated impairment of endothelial and
nitrergic relaxations that is related to a highly
defective NO/cGMP pathway. This would explain
why PDE-5 inhibitors, which act by potentiat-
ing the endogenous NO/cGMP signaling fail to
produce a therapeutic response as good as
that achieved in patients with less impacted
NO/cGMP pathway. Among the mechanisms
leading to a so impaired NO/cGMP pathway in
diabetes, the reduction of NO bioavailability due