Page 97 - 79_02

Long-­-life
supplementation
with
atenolol…

Docosahexahenoic
acid
(22:6n-­-3)
has
six
double
bonds
and
consequently
has

five
bis-­-allylic
hydrogens
per
chain,
and
is
320-­-times
more
susceptible
to
ROS
attack

than
oleic
acid
(18:1n-­-9),
which
is
consistent
with
the
strong
decrease
in
secondary

protein
lipoperoxidation
observed
(lower
MDAL
and
CML
in
AT-­-treated
animals).
In

our
case,
a
most
relevant
factor
that
contributed
to
decrease
the
DBI
and
PI
seems
to

be
the
strong
decrease
in
ß-­-peroxisomal
lipoxidation
(estimated
as
the
22:6n-­-
3/24:6n-­-3
ratio)
in
the
atenolol
group.
The
main
function
of
this
process
seems
to
be

the
partial
degradation
of
very-­-long
chain
fatty
acids,
producing
chain-­-shortened

acyl-­-CoAs,
acetyl-­-CoA
and
NADH,
which
may
exit
from
peroxisomes
via
pores
that

permit
the
influx
of
substrates
and
efflux
of
products
of
ß-­-oxidation.
These
substrates

go
back
to
the
mitochondria
to
complete
the
fatty
acid
oxidation
process
(47).

The
decrease
in
DBI
and
PI
confers
higher
resistance
of
membranes
to
lipid

peroxidation
and
lowers
lipoxidation-­-dependent
damage
to
macromolecules,
like

proteins,
and
(likely)
mtDNA.
The
long-­-term
atenolol
treatment
was
able
to
very

strongly
and
significantly
decrease
protein
oxidation
(GSA
and
AASA),
glycoxidation

(CEL
and
CML)
and
lipoxidation
(CML
and
MDAL)
markers
in
both
tissues,
except
for

CEL
in
SKM
which
also
showed
a
trend
to
decrease
that
did
not
reach
statistical

significance.
Aging
is
known
to
increase
protein
oxidation
in
association
with
a

functional
decline
of
proteasome
activity
(48)
whereas
decreases
in
protein
oxidation

and
increases
in
the
catabolism
of
modified
proteins
have
been
described
in

experimental
modifications
that
extend
longevity,
like
dietary
restriction
(49)
and

methionine
restriction
(50,
33)
even
when
applied
to
old
animals
(51).
The

decreased
fatty
acid
unsaturation
degree
most
likely
leads
to
a
lower
lipid-­-derived

secondary
free
radical
formation,
decreased
specific
protein
oxidation
and
damage
to

other
macromolecules
(52)
which
was
reflected,
in
our
case,
in
the
decrease
in

protein
oxidation,
glycoxidation
and
lipoxidation,
as
well
as,
in
the
case
of
the
heart,

mtDNA
oxidative
damage.

The
molecular
mechanism
suggested
to
explain
these
changes
could
be
the

following:
binding
of
hormones
and
neurotransmitters
to
ß-­-adrenergic
receptors

activates
adenylate
cyclase
(AC)
increasing
cyclic
adenosine
monophosphate
(cAMP)

and
then
protein
kinase
A
(PKA).
PKA
inhibits
Raf-­-1,
which,
in
turn,
stimulates
p-­-MEK

and
p-­-ERK.
p-­-ERK
enters
the
nucleus,
where
it
can
modify
gene
expression
through

the
action
of
many
different
molecules.
Because
AC
stimulates
PKA,
and
PKA
inhibits

Raf-­-1,
an
increase
in
the
Raf/MEK/ERK
pathway
is
expected
when
AC
is
lacking
or
ß-­-
adrenergic
receptors
are
blocked.
In
agreement
with
this,
an
increase
in
p-­-MEK
and

p-­-ERK
was
observed
in
tissues
of
AC5KO
mice,
including
the
heart
(1).
The
same

happens
in
our
pharmacological
model
of
ß-­-adrenergic
blockade
by
atenolol,
in

which
p-­-ERK
levels
were
increased
both
at
short-­-term
in
the
mice
heart
(2),
as
well

as
in
the
present
study
after
long-­-life
AT
treatment
in
heart
and
SKM
mitochondria.

This
protein
can
enter
the
nucleus
and
activate
different
transcription
factors,

267