CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 4, May 2012
222
AFRICA
Review Article
Endothelial dysfunction: the early predictor of
atherosclerosis
MASHUDU MUDAU, AMANDA GENIS, AMANDA LOCHNER, HANS STRIJDOM
Abstract
Since the discovery in the 1980s that nitric oxide (NO) is in
fact the elusive endothelium-derived relaxing factor, it has
become evident that NO is not only a major cardiovascular
signalling molecule, but that changes in its bioavailability are
crucial in determining whether atherosclerosis will develop
or not. Sustained high levels of harmful circulating stimuli
associated with cardiovascular risk factors such as diabe-
tes mellitus elicit responses in endothelial cells that appear
sequentially, namely endothelial cell activation and endothe-
lial dysfunction (ED).
ED, characterised by reduced NO bioavailability, is now
recognised by many as an early, reversible precursor of
atherosclerosis. The pathogenesis of ED is multifactorial;
however, oxidative stress appears to be the common under-
lying cellular mechanism in the ensuing loss of vaso-active,
inflammatory, haemostatic and redox homeostasis in the
body’s vascular system. The role of ED as a pathophysi-
ological link between early endothelial cell changes associ-
ated with cardiovascular risk factors and the development
of ischaemic heart disease is of importance to basic scientists
and clinicians alike.
Keywords:
endothelium, endothelial dysfunction, nitric oxide
bioavailability, eNOS uncoupling, oxidative stress, atheroscle-
rosis
Submitted 7/6/11, accepted 11/11/11
Cardiovasc J Afr
2012;
23
: 222–231
DOI: 10.5830/CVJA-2011-068
Between 1995 and 2004, cardiovascular diseases accounted for
about 195 deaths per day in South Africa. Particularly disturbing
is that cardiovascular mortality is expected to escalate by a
staggering 41% in the working age group (35–64 years) in the
South African population by the year 2030.
1
In 2004, the World
Health Organisation (WHO) reported cardiovascular diseases/
ischaemic heart disease (IHD) to be the leading cause of death
worldwide and that cardiovascular deaths are envisaged to
escalate to 23.4 million by the year 2030.
2
Atherosclerosis is a chronic progressive vascular disease,
characterised by plaque formation and subsequent fissure,
erosion or rupture of the plaque with thrombosis of the plaque
surface.
3
A complication of coronary atherosclerosis can be the
development of myocardial ischaemia and ultimately myocardial
infarction.
4
Hypertension, tobacco use, dyslipidaemia, diabetes
mellitus, physical inactivity and obesity, all of which are
associated with the development of atherosclerosis and IHD, are
considered to be the top risk factors for cardiovascular mortality
worldwide.
2
Chronic exposure to cardiovascular risk factors and the
harmful circulating stimuli associated with these conditions
overwhelms the defense mechanisms of the vascular endothelium,
hence compromising its integrity and ultimately initiating
endothelial dysfunction (ED).
5
Mounting evidence is pointing
to ED as one of the major pathophysiological links between
exposure to cardiovascular risk factors and the development of
atherosclerotic disease (Fig. 1).
6
ED is commonly associated with reduced nitric oxide (NO)
bioavailability, and hence an inability of the endothelium to
Department of Biomedical Sciences, Division of Medical
Physiology, Faculty of Health Sciences, Stellenbosch
University, Stellenbosch, South Africa
MASHUDU MUDAU, MSc
AMANDA GENIS, MSc
AMANDA LOCHNER, PhD
HANS STRIJDOM, BMedSc, MB ChB, PhD,
EXPOSURE TO CARDIOVASCULAR RISK FACTORS:
• Hyperglycaemia/insulin resistance (diabetes mellitus)
• Smoking
• Hypertension
• Obesity
• Hyperlipidaemia
PROGRESSION TO ATHEROSCLEROSIS:
• Plaque formation and sequelae
• Myocardial ischaemia
• Myocarial infarction
DEVELOPMENT OF ENDOTHELIAL CELL CHANGES:
• Endothelial activation
• Endothelial dysfunction
Associated with reduced NO bioavailability;
pro-vasoconstriction; pro-oxidative stress;
pro-coagulation; pro-inflammation
If sustained and not reversed
If sustained and not reversed
Fig. 1. Exposure of endothelial cells to cardiovascu-
lar risk factors and the resultant pathophysiological
changes, i.e. endothelial activation and dysfunction, with
progression to atherosclerosis if risk-factor exposure is
sustained.
