CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 10, November 2012
AFRICA
567
pro-inflammatory cytokines but also secretes a host of bioactive
molecules including angiotensinogen, leptin, resistin, adiponectin
and PAI-1, which influence the function and structural integrity
of the cardiovascular system.
76,77
These adipocytokines influence
glucose metabolism, blood pressure regulation, lipid metabolism,
the coagulation system and endothelial function to accelerate the
process of atherosclerosis.
Obesity is strongly associated with cardiovascular disease and
promotes the clustering of risk factors such as dyslipidaemia,
hypertension, diabetes and the metabolic syndrome. Obese
individuals experience substantially elevated morbidity and
mortality from all forms of cardiovascular disease.
78,79
A retrospective analysis of the Bogalusa Heart Study
examined the relationship between weight change and telomere
dynamics over a period of 10 to 12 years in 70 young adults. The
study showed that weight gain was associated with accelerated
telomere attrition and that a rise in insulin resistance accounted
for the relationship between the increase in body mass index
(
BMI) and telomere attrition rate.
22
In the study by Valdes
et al
.
of 1 122 healthy adult female
twins (45 monozygotic and 516 dizygotic pairs, mean age 47
years), it was found that the telomeres of obese twins were 240
base pairs shorter than those of the lean sibling. The difference
in telomere length between the lean and the obese corresponded
to 8.8 years of ageing.
19
The study also suggested that the
mechanism by which obesity affects telomere length is through
increased leptin levels rather than BMI
per se
.
Obesity is associated with high serum concentrations of
leptin, which is linked to NF-
κ
B activation, a mediating factor in
the production of ROS and inflammatory cytokines.
80
Nordfjall
et al
.
confirmed the negative association between BMI and
telomere length but in their study, this finding applied only to
female participants.
81
Insulin resistance
Insulin resistance is pro-atherogenic and increases the risk of CAD
even without the presence of hyperglycaemia.
82
The mechanisms
involved in atherogenesis include both systemic effects such
as dyslipidaemia, hypertension and a pro-inflammatory state
as well as direct effects on vascular endothelial cells, smooth
muscle cells and macrophages. These three cell types have
insulin receptors and effects are mediated via down-regulation of
insulin signalling pathways such as the Akt pathway.
In early atherosclerosis, insulin resistance causes decreased
nitric oxide production and an increase in VCAM-1, which
are responsible for impaired vasodilation and inflammation.
In advanced plaques, insulin resistance triggers apoptosis of
cells via the Akt pathway.
83-86
Apoptosis of smooth muscle cells
causes fibrous cap thinning, whereas apoptosis of macrophages
leads to plaque necrosis, both being pathological processes that
precipitate acute coronary syndromes.
Diabetes
In the setting of type 2 diabetes, insulin resistance and
hyperglycaemia have additive effects that accelerate the
process of atherosclerosis. Hyperglycaemia is associated with
the activation of several molecular pathways that include the
production of advanced glycation end products (AGEs),
87,88
activation of protein kinase C, increased activity of both the
polyol as well as the hexosamine pathways.
89,90
These pathways
are interdependent and induce cellular damage through the final
common mechanism of increased oxidative stress.
It is well established that hyperglycaemia, even in the
pre-diabetic state, induces oxidative stress
91-94
and ultimately leads
to cellular senescence. Cellular senescence and apoptosis occur
not only in vascular endothelial and smooth muscle cells but
in multiple cell lines, including endothelial progenitor cells.
95,96
Type 2 diabetes can therefore be considered a premature-ageing
syndrome.
In recent years several cross-sectional clinical studies have
been published that demonstrate an association between shorter
telomere length and type 2 diabetes (T2D).
23-26,97-99
The studies
suggest that there is a gradation in the severity of telomere
shortening. Shorter telomere lengths were noted in patients
with impaired glucose tolerance compared to controls, even
shorter lengths in those with diabetes, and the shortest lengths
were observed in patients with the combination of pre-diabetes/
diabetes and atherosclerotic vascular disease, compared to those
with diabetes or cardiovascular disease alone.
100
Satoh
et al
.
showed that CAD patients with the metabolic
syndrome had shorter telomeres than CAD patients without
the metabolic syndrome.
97
Adaikalakoteswari
et al
.
found that
among diabetic patients, those with atherosclerotic plaques had
shorter telomeres.
98
The study by Olivieri
et al
.
demonstrated
that diabetic patients with myocardial infarction had shorter
telomeres than diabetic subjects without myocardial infarction,
99
and the study by Salpea
et al
.
showed that among diabetic
subjects, those with CAD had significantly shorter telomeres.
26
Based on these observations, it has been postulated that
critically shortened telomeres, due to a combination of inherited
short telomeres and oxidative stress-induced telomere attrition,
caused by the common risk factors between diabetes and
cardiovascular disease, indicates greater cellular ageing in
vascular endothelial cells and pancreatic beta-cells, and may be
a useful biomarker of tissue ageing and disease progression.
100
Atherosclerosis and coronary artery disease
Minamino
et al
.
have shown that endothelial cells with
characteristic features of senescence are present in atherosclerotic
regions of human coronary arteries. They demonstrated that
inhibiting telomere function induced senescence in endothelial
cells, whereas introducing telomerase suppressed senescence
and extended the lifespan of these cells.
3
Ogami
et al
.
have shown that the telomeres of coronary
endothelial cells were shorter in patients with CAD compared to
age-matched subjects without CAD and that in the CAD patients,
telomere length was shorter in endothelial cells at atherosclerotic
sites compared to non-atherosclerotic sites.
101
Chang and Harley
have shown that endothelial cells in regions of the vascular tree
that are subjected to greater haemodynamic stress demonstrated
more pronounced telomere attrition than endothelial cells from
areas with less shear stress. For example, telomere attrition rate
in the iliac arteries was –147 base pairs per year compared to the
internal mammary arteries at –87 base pairs per year.
102
Okuda
et al
.
also demonstrated that telomere attrition was
higher in the intima of the distal abdominal aorta compared
to the proximal abdominal aorta, again indicating that areas
of the vasculature that undergo greater shear wall stress have
