CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 10, November 2012
566
AFRICA
There is currently much interest in the development of Akt
inhibitors for the treatment of cancer and it remains to be seen
what effects such therapy would have on the cardiovascular
system. In addition to Akt signalling, mitogenic stimuli
may activate Ras signalling, which has also been shown to
participate in the divergent processes of both cell proliferation
and senescence.
66
Oxidative stress and telomere shortening
Exposure of DNA to oxidative stress produces higher levels of
stress biomarkers in telomere sequences than in non-telomere
sequences. 8-oxodG (8-oxo-7,8-dihydro-2-deoxyguanosine) is
a sensitive biomarker for oxidative stress on DNA. Progressive
increases in 8-oxodG have been shown to correlate with
decreasing telomere length. The high guanine (-GGG) content
of telomeres makes them particularly sensitive to damage by
oxidative stress.
47,67
This site specificity for guanine is due to several reasons.
Firstly, guanine is the most easily oxidised DNA base as
its oxidation potential is lower than that of the other three
bases (adenine
<
cytosine
<
thymine). A second factor is the
distribution of electrons on the DNA base. The highest occupied
molecular orbital that accommodates electrons with the greatest
energy determines the reactivity of DNA bases. Many of these
electrons are located on the 5
′
-
G of the GG sequence and
therefore this guanine is more likely to be oxidised.
A third reason is that the ROS have different redox potentials,
which may determine site specificity. For example, the free
hydroxyl radicals cause DNA damage without a marked site
specificity, whereas the benzoyloxyl radicals specifically
cause damage to the 5
′
-
G in GG sequence.
68-70
In addition to
the direct effects of ROS, telomeres, unlike the rest of the
genome, appear less efficient in repairing oxidative damage.
71
An
important consequence of oxidative stress is the initiation of an
inflammatory response.
Inflammation and telomere shortening
Chronic systemic inflammation is responsible for an increase
in peripheral white blood cell turnover, which in turn leads to
an exaggerated telomere attrition rate.
55
The increased white
cell consumption induces haematopoietic stem cells to divide,
thereby shortening their telomere length as well. Exposure to
TNF-
α
also reduces telomere length by negative regulation of
telomerase activity.
57
DNA sampling for telomere length quantification is generally
sourced from circulating white blood cells rather than human
vascular tissue. It has been suggested that white blood cell
telomere attrition is a consequence of systemic inflammation
rather than being indicative of vascular endothelial cell ageing.
The study by Wilson
et al
.
demonstrated that telomere attrition
in circulating blood leucocytes reflects similar changes in the
vasculature and is an acceptable surrogate for vascular ageing in
population studies.
72
Mechanisms of repair: stem cells and
endothelial progenitor cells
The atherosclerotic process is characterised by endothelial
cell dysfunction. Repair of the endothelium is dependent on
the presence of endothelial progenitor cells, which migrate to
sites of vascular injury to initiate repair. Endothelial progenitor
cells are produced by haematopoietic stem cells, which, due
to their higher telomerase activity, have a greater proliferative
capacity. Exhaustion of the progenitor cell or stem cell pool is an
important factor in endothelial cell dysfunction. Telomere length
in haematopoietic stem cells (HSC) is a reflection of progenitor
cell reserves, and shortened telomere length in these cells is
indicative of diminished reparative capacity.
41,42
The onset of atherosclerotic disease is therefore dependent
on the balance between injury and repair of the endothelium –
injury from oxidative stress and inflammation, and repair, which
depends on haematopoietic stem cell reserves, as reflected by
HSC telomere length.
41
Telomeres and atherosclerosis risk factors
Smoking
Cigarette smoking is associated with increased oxidative
stress.
73
Although there is variability in the findings of different
epidemiological studies, the following studies recorded an
association between smoking and telomere shortening. Nawrot
et al
.,
reporting on the Flemish study on environment, genes and
health outcomes, found shorter telomeres in smokers compared
to non-smokers.
45
The study by Valdes
et al
.
showed that women
who had never smoked had longer telomeres than former
smokers, and both had longer telomeres than current smokers
(531
never smokers, 369 ex-smokers and 203 current smokers).
They also demonstrated a dose-dependent relationship
between smoking and telomere shortening. Each pack-year
smoked was equivalent to the loss of an additional five base
pairs of telomere length, or 18% of the average annual loss in
telomere length, compared to the rate in the overall cohort.
19
The dose-effect relationship was subsequently replicated by
Morla
et al
.
who studied a cohort of male smokers with and
without chronic obstructive pulmonary disease (50 smokers, 26
never smokers) in whom telomere shortening correlated with
cumulative exposure to tobacco smoking.
20
Hypertension
Since systolic blood pressure rises with age, and diastolic blood
pressure plateaus, Jeanclos
et al
.
postulated that arterial pulse
pressure may correlate with biological age. Among 49 twin pairs
(
mean age 37 years) in the Danish Twin Register, they showed
a significant inverse correlation between pulse pressure and
telomere length, i.e. wider pulse pressure was associated with
shorter telomere length.
74
The Framingham Heart Study found shorter telomere lengths
in hypertensive males (
n
=
171)
compared to their normotensive
peers (
n
=
156)
but the shorter telomere length was largely due
to insulin resistance.
21
Benetos
et al
.
examined the relationship
between telomere length and carotid artery atherosclerosis in
163
treated hypertensive males and found that telomere length
was shorter in hypertensive men with carotid plaques compared
to hypertensive men without plaques.
75
Obesity
Increased caloric intake and obesity are recognised to shorten
lifespan. Adipose tissue is not only a source of ROS and
