CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 4, May 2012
AFRICA
229
anti-ED therapies. We are not there yet. The various endothelial
function assessment tools at our disposal should be compared
in studies that account for, among others, pathophysiological
relevance and reproducibility, predictability in diverse patient
populations, ease of use, cost-effectiveness, and risk assessment
abilities that are superior to the tools currently in use.
85
Another shortcoming in our understanding of the clinical
significance of ED is the lack of studies where the effects
of therapies that specifically target endothelial biology are
investigated. In this regard, promising observations were made
in a study which showed that dietary supplementation with
the NO-donor, L-arginine significantly improved endothelium-
dependent dilatation inyoungadultswithhypercholesterolaemia.
87
Similarly, in another study on rabbits, dietary supplementation
with L-arginine prevented hypercholesterolaemia-induced ED by
augmentation of NO-production.
88
Progression of ED to atherosclerosis
ED has emerged as a potentially valuable prognostic tool in
predicting the development of atherosclerosis and ultimately
IHD.
89
The progression from the early changes observed in
compromised vascular endothelium (endothelial activation and
dysfunction) to atherosclerosis is complex and multifactorial.
89
The healthy, intact endothelium is a highly selectively
permeable barrier and does not promote leukocyte adhesion
and invasion, or platelet aggregation and adhesion.
53
However,
as the endothelium progresses to a dysfunctional state, vascular
homeostasis becomes impaired, leading to reduced anti-oxidant,
anti-inflammatory and anti-thrombotic properties (due to reduced
NO bioavailability), enhanced endothelial permeability (barrier
dysfunction), upregulated pro-inflammatory cytokine levels, and
expression of adhesion molecules such as VCAM-1 and ICAM-
1, which facilitate leukocyte adhesion to the endothelium.
53
Leukocyte adhesion represents one of the first steps in the
initiation of atherosclerosis. After adhering to the endothelium,
leukocytes (monocytes and lymphocytes) cross the endothelium
and migrate into the intima.
54,90
Migration to the intima is
mediated by chemo-attractants such as monocyte chemotactic
protein-1 (MCP-1).
91
Upon reaching the intima, monocytes
transform into macrophages and express receptors that facilitate
uptake of lipids. Uptake and accumulation of lipids lead to
the transformation of macrophages into foam cells, which
initiate an atherosclerotic lesion and further enhance release of
inflammatory cytokines.
54,90
Through these complex mechanisms,
a cascade of events, which begins with the formation of an
early atherosclerotic lesion, leading to an advanced lesion
characterised by a plaque formation ensues.
90
Anti-endothelial dysfunction therapies
It has been shown that interventions such as lifestyle modification
(exercise and diet) and various classes of pharmacological drugs
can improve endothelial function, and in some instances reduce
the risk of cardiovascular diseases.
22,92
The anti-ED properties of
statins have been extensively studied. Statins such as pravastatin,
atorvastatin, simvastatin and fluvastin have all been shown
to play an important role in correction of ED by improving
endothelium-dependent vasodilation, in addition to their plasma
cholesterol-lowering effects.
33
Indeed, statin-induced eNOS activating effects have been
demonstrated in investigations where addition of an eNOS
inhibitor (L-NMMA) to pravastatin-treated hypercholesterol-
aemic patients hampered the endothelium-dependent
vasodilation.
93
Moreover, statins have been reported to stimulate
activity of PKB/Akt, a major upstream activating signalling
molecule of eNOS, and increase stability of eNOS mRNA, thus
enhancing eNOS expression.
33
In addition to statins and NO donors (discussed above), other
drugs that have been shown to improve endothelial function
include angiotensin converting enzyme (ACE) inhibitors,
angiotensin receptor (AT1 receptor) blockers, peroxisome
proliferator-activated receptor-
γ
(PPAR-
γ
) agonists, antioxidants
and oestrogen replacement.
22,92
In a recent review article,
Balakumar
et al.
identified potentially novel target sites for the
pharmacological improvement of vascular function.
64
These target
sites include rho-kinase, poly (ADP ribose) polymerase, protein
tyrosine phosphatase (PTPase), Akt, protein kinase A (PKA),
caveolin, cholesterylester transfer protein (CETP), lipoprotein
lipase, sphingosine-1-phosphate (S1P), advanced glycation
end-product (AGE) and transketolase, geranylgeranyltransferase
(GGT), epoxide hydrolase and Janus kinase (JAK).
Conclusion
In view of the ever-increasing prevalence of ischaemic heart
disease in the developed and developing world, it has become
imperative to identify and investigate mechanisms of early,
potentially reversible pre-atherosclerotic changes in the
endothelium. To date, the most clearly defined and well-
understood early precursor of atherosclerosis is ED. In fact
ED can be regarded as the
primum movens
of atherosclerotic
disease. Several cellular mechanisms and markers of ED that
could potentially lead to the development of early detection
and therapeutic interventions have been determined. However,
more research aiming at improving our understanding of ED
is necessary in order to establish its detection and reversal as
essential and routinely utilised future tools in the prevention of
IHD.
This study was sponsored in part by the Medical Research Council (MRC) of
South Africa, National Research Fund (NRF) of South Africa and the Harry
Crossley Foundation, University of Stellenbosch.
References
1.
Steyn K. Heart Disease in South Africa. In: Fourie JM (ed). Chronic
diseases of lifestyle unit. Medical Research Council (MRC) media data
document. MRC, 2007.
2.
World Health Organisation (WHO). Global health risks: Mortality and
burden of disease attributable to selected major risks. Geneva: WHO,
2009.
3.
Lahoz C, Mostaza JM. Atherosclerosis as a systemic disease.
Rev Esp
Cardiol
2007;
60
(2): 184–195.
4.
Choi D, Hwang K-C, Lee K-Y, Kim Y-H. Ischemic heart disease:
current treatments and future.
J Contr Release
2009;
140
: 194–202.
5.
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and
dysfunction: Testing and clinical relevance.
Circulation
2007;
115
:
1285–1295.
6.
Yang G, Lucas R, Caldwell R, Yao L, Romero MJ, Caldwell RW. Novel
mechanisms of endothelial dysfunction in diabetes.
J Cardiovasc Dis
Res
2010;
1
(2): 59–63.
7.
Chhabra N. Endothelial dysfunction – A predictor of atherosclerosis.
Internet J Med Update
2009;
4
(1): 33–41.
8.
Bijl M. Endothelial activation, endothelial dysfunction and premature
