Reduction in mitochondrial membrane peroxidizability index…
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In the AC5KO model, extension of lifespan in 129/SvJ-‐C57BL/6 mice has
been obtained through the disruption of the β-‐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 β-‐adrenergic
receptor blocking. Atenolol is a second generation β-‐blocker with selectivity for
cardiac β1 receptors. β1 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 β1-‐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 β1-‐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 β1-‐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
