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46
64
Ya
amada A1, To
orimoto K1, Matsuyoshi
M
H2, Obata K2, Guo-xing Z2, Hirayama A1, Fujimotoo K1, Hirao Y1, Takaki M2
1. Department of Urology, Nara
N
Medica
al University, 2. Departme
ent of Physio
ology II, Naraa Medical Un
niversity
Ch
haracteris
stic Findings of Blad
dder Func
ction in SE
ERCA2a-Transgenicc Rats
Hypothesis / aim
ms of study
The
e contractile a
activity of smooth muscle de
epends on intrracellular Ca2++ concentration
n, which is reggulated by the activities of
cha
annels, transp
porters and pumps at cell an
nd organellar m
membranes. Sarco/endopla
S
asmic reticulum
m Ca2+-ATPas
se (SERCA) 2 is
res
sponsible for lo
owering Ca2+, leading to relaxation of smo
ooth muscle. Similar
S
molecular mechanissm to cardiac muscle seem
ms
to act
a in bladder smooth musccle. However, in cardiac musscle, SERCA2
2 down-regulation occurs in the rat hyperttrophy model [1],
whereas it was rreported that th
he deletion of a pair of SER
RCA2 allele protected bladder against hyppertrophy in a murine model of
parrtial bladder ou
utlet obstructio
on [2]. The aim
m of the prese
ent study was to reveal the role
r
of SERCA
CA2 in formatio
on of bladder
hyp
pertrophy usin
ng female SER
RCA2a-transgenic rats (TG)) and wild-type
e rats (WT).
udy design, ma
aterials and methods
m
Stu
A to
otal of 15 female Wistar ratss (TG:10; WT::5) were used in this study. Under halotha
ane anesthesiaa, a polyethyle
ene catheter
(PE
E-50) with a cu
uff was implan
nted into the dome
d
of bladde
er through an abdominal inc
cision. Cystom
metry was perfformed in
con
nscious condittions. Basal prressure (BP: the
t lowest pre
essure during filling),
f
thresho
old pressure (T
TP: pressure just
j
before
mic
cturition contra
action), maxim
mum pressure (MP: maximu
um pressure during micturition), and mictuurition interval (MI: interval
bettween each m
micturition conttraction) were measured. Affter cystometry
y the rats were
e sacrificed annd the bladderrs were
rem
moved. Membrane proteins were used forr Western blott analysis usin
ng a SERCA2 specific monooclonal antibod
dy.
Results
In cystometry,
c
there were no significant
s
diffe
erence in para
ameters betwe
een 10 TG and
d 5 WT groupss. However, th
he bladders in 4
of 10
1 TG rats appeared to be hypertrophic
h
and
a showed siignificantly sho
orter MI and significantly
s
higgher BP than other 6 TG an
nd
WT
T rats (P<0.05
5)(Fig. 1 and 2).
2 In these 4 TG
T rats, the exxpression of SERCA2
S
prote
ein was higherr than other 6 TG rats.
Inte
erpretation of results
The
e amount of S
SERCA2 prote
ein supposed to
t be depende
ent on homo or
o hetero condition of SERCA
CA2 gene in TG
G group. The
SE
ERCA2a-rich b
bladder showe
ed lower compliance and de
etrusor overacttivity while non
n-SERCA2a-rrich bladder did not,
sug
ggesting that tthe SERCA2-rrich bladder fu
unctionally ressembles hyperrtrophic bladde
er. The SERCA
CA2a-rich bladder showed
hig
gher vesical prressure after micturition
m
bec
cause the relaxxation function
n of bladder may
m have beenn impaired, res
sulting in
inc
creased micturrition frequenccy.
Concluding messsage
Ov
verexpression of SERCA2 in
n bladder affec
cted bladder fu
unction, induc
cing lower com
mpliance and ddetrusor overa
activity. The
fun
nctional changes partially resembled hype
ertrophic bladd
der induced by
y its outlet obs
struction. The intervention in
n SERCA2rela
ated pathway can be a nove
el treatment fo
or bladder hyp
pertrophy if we
e could demon
nstrate that ovverexpression of SERCA2
acc
celerates form
mation of bladd
der hypertroph
hy induced by partial outlet obstruction.
o
References
1. Aoyagi T et al. The sarcop
plasmic reticulum Ca2+-AT Pase (SERCA
A2) gene prom
moter activity iss decreased in
n response to
ad hypertrophyy in rat hearts.. J Mol Cell Ca
ardiol. 1999 A
Apr;31(4):919-2
26.
severe left vventricular pressure-overloa
2. Jenny Lassm
mann et al. De
eletion of one SERCA2 alle le confers pro
otection agains
st bladder walll hypertrophy in a murine
model of partial bladder outlet
o
obstruction. Am J Phyysiol Regul Inte
egr Comp Phy
ysiol 294: R588–R65, 2008.
Spe
ecify source off funding or grrant
Is this
t
a clinical trrial?
Wh
hat were the su
ubjects in the study?
s
We
ere guidelines ffor care and us
se of laboratory
y animals follo
owed
or ethical
e
committtee approval obtained?
o
Nam
me of ethics co
ommittee
This work
w
was supp
ported by Gran
nts-in-aid for Sc
cientific
Resea
arch(21791525,22591798) fro
om Ministry of Education,
E
Scien
nce, Sports and
d technology o
of Japan.
No
ANIMAL
Yes
the an
nimal care of use
u committee of Nara Medical University