Page 99 - 79_04

Reduction
in
mitochondrial
membrane
peroxidizability
index…

In
the
AC5KO
model,
extension
of
lifespan
in
129/SvJ-­-C57BL/6
mice
has

been
obtained
through
the
disruption
of
the
ß-­-adrenergic
receptor
signaling
at
the

Type
5
adenylyl
cyclase
(AC5)
level
(1).
This
AC5KO
knockout
mouse
showed

increased
mean
and
maximum
longevity,
from
25
to
33
months
and
from
33
to
37

months,
respectively;
and
also
showed
improvements
in
the
cardiomyopathy
and

bone
deterioration
related
to
aging.
The
disruption
of
AC5
preserved
cardiac

function
in
response
to
chronic
pressure-­-overload
and
catecholamine
stress,
which

is
known
to
play
a
major
role
in
heart
failure
development
(21).
These

improvements
seemed
to
be
signaled
in
the
cell
due
to
an
increase
in
the

Raf/MEK/
extracellular
signal-­-regulated
kinase
(ERK)
pathway
as
suggested
by

increases
in
the
amount
of
the
p-­-MEK
and
p-­-ERK
in
various
tissues,
including

heart,
of
AC5
KO
mice
(1).
These
mice
also
had
higher
levels
of
the
antioxidant

enzyme
manganese
superoxide
dismutase
(MnSOD)
in
heart,
kidney
and
brain,

suggesting
that
a
decrease
in
oxidative
stress
could
be
involved
in
the
mechanisms

responsible
for
the
aging
delay
effect.

Taking
all
these
into
account,
it
was
interesting
to
test
if
the
two
main

oxidative
stress-­-linked
factors
related
to
longevity,
the
mitROS
generation
rate
and

the
fatty
acid
unsaturation
degree,
were
also
lowered
in
animals
with
ß-­-adrenergic

receptor
blocking.
Atenolol
is
a
second
generation
ß-­-blocker
with
selectivity
for

cardiac
ß1
receptors.
ß1
receptors
are
predominantly
located
in
cardiac
tissue
and

primarily
stimulated
by
norepinephrine;
they
are
coupled
to
AC
through
a

stimulatory
G
protein.
From
the
different
AC
subtypes,
AC5
is
the
main
type
in

cardiac
tissue.
Therefore,
blocking
the
ß1-­-receptors
can
afford
a
fast
and

convenient
model
that
could
potentially
mimic
the
phenotype
of
the
AC5KO

rodents.
In
the
present
study
we
tested
the
effect
of
the
ß1-­-selective
blocker

atenolol
in
Wistar
rats
(genetically
heterogeneous
animals,
like
human
beings)
to

investigate
if
this
drug
also
increases
Raf/MEK/ERK
signaling
and
whether
or
not

the
beneficial
effects
of
ß1-­-receptor
blocking
are
also
due
to
decreases
in
oxidative

stress
as
it
has
been
initially
suggested.(1)
We
hypothesized
that
atenolol
also

increases
Raf/MEK/ERK
signalling
in
rats
and
that
the
mechanism
responsible
for

its
effects
includes
lowering
one
or
both
known
factors
related
to
longevity:

mitROS
production
and
the
degree
of
fatty
acid
unsaturation.
The
possible

beneficial
effects
of
atenolol
could
be
important
because
atenolol
treatment
in

humans
would
be
easier
to
implement
than
dietary
restriction
models.

In
the
present
investigation,
and
for
that
purpose,
we
measured
the

mitochondrial
ROS
generation
rate,
mitochondrial
oxygen
consumption
in
states
4

(resting)
and
3
(phosphorylating),
the
percent
free
radical
leak
(%FRL)
in
the

respiratory
chain,
the
respiratory
complex
I
to
IV
amounts,
and
the
content
of
the

antioxidant
enzyme
MnSOD.

We
also
studied
the
apoptosis-­-inducing
factor
(AIF)

because
it
can
stimulate
apoptosis,
but
it
is
also
required
for
the

615