ARTICLE
Exercise and Atherogenesis
J. Kelly Smith
Division of Immunology, Department of Internal Medicine, James H. Quillen College of Medicine, East
Tennessee State University, Johnson City, Tennessee
SMITH, J.K. Exercise and atherogenesis. Exerc. Sport Sci. Rev., Vol. 29, No. 2, pp 49 –53, 2001. Atherogenesis involves the
activation of endothelial cells and the egress of atherogenic T lymphocytes and monocytes into the intima. Exercise training contributes
to the arrest and even reversal of atherosclerosis by modifying risk factors and by inducing an atheroprotective phenotype in endothelial
cells and T cells. Keywords: T cells, cytokines, endothelium
INTRODUCTION
Although there has been a decline in the age-adjusted
death rate from cardiovascular disease (CVD) in the past 25
yr, heart disease remains the leading cause of death in the
United States, accounting for 733,834 deaths, or 31.6% of
total mortality, in 1996 (12). Overall, CVD accounts for
more than 40% of deaths in the industrialized nations of the
western world.
A number of studies have shown that moderate-intensity
physical activity reduces the incidence of all-cause mortality,
particularly deaths due to CVD (2). The accumulated evi-
dence on the health benefits of physical activity prompted
participants in a National Institutes of Health Consensus
Conference to recommend that “children and adults alike
should set a goal of accumulating at least 30 min of moderate-
intensity physical activity on most, and preferably all, days of
the week” (13).
Despite the documented health benefits, the mechanism
whereby physical activity prevents CVD is incompletely un-
derstood, although it is probably multifactorial. Risk factors
such as hypertension, obesity, hyperlipidemia, and insulin
resistance may respond favorably to moderate levels of phys-
ical activity, thereby protecting against CVD (5). Because
exercise also protects against CVD in smokers and in persons
without evident risk factors (2), however, it appears to fa-
vorably influence the course of atherogenesis in ways yet to
be discovered. Whatever the reasons, reports have docu-
Address for correspondence: J. Kelly Smith, M.D., Department of Internal Medicine,
James H. Quillen College of Medicine, East Tennessee State University, Johnson City,
TN 37614. (E-mail: smithj@etsu.edu).
Accepted for publication: October 13, 2000.
0091-6631/2902/49 –53
Exercise and Sport Sciences Reviews
Copyright © 2001 by the American College of Sports Medicine
49
mented a strong and independent association of low cardio-
respiratory fitness and low levels of physical activity and the
risk of death due to CVD (2).
This review will examine what is currently known about
the immunopathogenesis of atherosclerosis and provide some
insight into how physical activity may favorably alter the
course of the disease by affecting the function of vascular
endothelium, monocytes, and T lymphocytes.
ATHEROSCLEROSIS: AN INFLAMMATORY DISEASE
There is convincing evidence that atherosclerosis is an im-
munologically mediated inflammatory disease (10). Atheroscle-
rotic lesions contain activated immune cells, including CD4⫹
and CD8⫹ T cells, monocytes, macrophages, and endothelial
cells. These cells are responsible for the local production of a
variety of cytokines that have been identified in atherosclerotic
lesions, including interleukin (IL)-1, IL-2, IL-4, IL-6, IL-10,
tumor necrosis factor-␣ (TNF-␣), interferon-␥ (IFN-␥), and
transforming growth factor-␤ (TGF-␤). There is provocative
but as yet inconclusive evidence that this immune reaction may
be in response to an infectious agent, heat shock protein (HSP)
60, and/or oxidized LDL (14). Whatever the inciting event(s),
in transplanted human hearts, activation of coronary endothe-
lial cells is predictive of the subsequent development of coronary
atherosclerosis (9), lending credence to the importance of the
immune response in the early stages of CVD. Indirect evidence
is also found in reports documenting an association between
blood levels of acute-phase reactants, notably C-reactive pro-
tein, fibrinogen, and the third component of complement, and
the future risk of heart attack (14). Acute-phase reactants are
produced by hepatocytes in response to several proinflammatory
cytokines, notably IL-1, IL-6, and TNF-␣, and often serve to
minimize tissue damage that follows an inflammatory response.
 Whereas there is general agreement that atherosclerosis is
due to a sustained inflammatory response involving activated
endothelial cells, T lymphocytes, and mononuclear phago-
cytes, some controversy remains about the nature of the
immunogen or immunogens that trigger and sustain this
immune response.
THE RESPONSE-TO-INJURY HYPOTHESIS
Current models of atherosclerosis are based primarily on
the “response-to-injury” hypothesis put forth in the early
1970s by Russell Ross and John Glomset of the University of
Washington. Much of the discussion to follow is based on
this model.
In the earliest stage of atherosclerosis, normal resting en-
dothelial cells are thought to be activated in response to the
injurious effects of toxic lipids, abnormally high or low he-
modynamic shear forces, infection with agents such as Chla-
mydia pneumoniae and cytomegalovirus, and/or smoking (10).
Activated endothelial cells upregulate their production of
adhesion molecules and chemokines, thereby augmenting
the adhesion and subsequent egress of mononuclear cells into
the subendothelium (Figure 1). The endothelium also stim-
ulates the growth of vascular smooth muscle cells by increas-
ing its production of growth factors while decreasing its
production of TGF-␤, a growth inhibitor. The endothelium
is dysfunctional, particularly with regard to its ability to
maintain normal vascular tone by secreting appropriate
amounts of its vasodilators, nitric oxide, prostacyclin PGI2,
C-type natriuretic peptide, and adrenomedullin, while min-
imizing its production of vasoconstrictors. In addition, as a
result of a decreased production of thrombomodulin, tissue-
type plasminogen activator, and nitric oxide, endothelial
procoagulant activity is increased. Activated endothelium
also augments its production of cytokines that promote en-
dothelial and vascular smooth muscle cell activation (IL-1),
acute-phase protein production (IL-6), and granulopoiesis
(colony-stimulating factors). Finally, endothelial cell produc-
50 Exercise and Sport Sciences Reviews
tion of antioxidant enzymes is compromised, resulting in an
increased rate of oxidation of phospholipids and nitric oxide.
Collectively, these functional changes are characteristic of an
atherogenic endothelial cell phenotype (11).
T helper type 1 (Th1) lymphocytes and their effector cells,
monocytes and macrophages, are the dominant cell type
egressing into the intima in atherosclerosis (6). Along with
endothelial and vascular smooth muscle cells, macrophages
have scavenger receptors for modified lipoproteins carrying
various oxidized phospholipids, enabling them to internalize
the receptor-lipid complexes in their phagosomes and to
digest them in their phagolysosomes (Figure 2). Peptides
derived from the lipoproteins are then transported to the
surface of the macrophages in the form of major histocom-
patibility complex (MHC) class II:peptide complexes, where
they can be presented to T lymphocytes. Armed Th1 cells
displaying T-cell receptors specific for the MHC II:peptide
complexes activate these macrophages by secreting IFN-␥, a
potent atherogenic cytokine, and by binding to CD40 ligands
present on the macrophages’ cellular membranes. Once ac-
tivated, macrophages are more efficient in ingesting, process-
ing, and presenting antigens, including other suspect athero-
genic immunogens such as HSP 60 and infectious agents, to
Th1 cells. They also secrete increased amounts of proinflam-
matory cytokines (TNF-␣, IL-1), chemokines that attract T
cells and monocytes (such as monocyte chemoattractant
protein-1 and IL-8), vascular smooth muscle cell growth
factors (platelet-derived growth factors), metalloproteinases,
and NADPH-derived reactive oxygen intermediates, all of
which contribute to the atherogenic process (10,11).
It should be noted that macrophages that have ingested a
microbe, such as C. pneumoniae, can activate naïve (resting) T
helper cells by displaying B7 coactivation molecules in conjunc-
tion with recognizable MHC II:peptide complexes (Figure 3).
Once activated, the T cells produce large amounts of IL-2 and
high-affinity IL-2 receptors and undergo clonal proliferation. In
the presence of IL-12, a growth factor produced by activated
macrophages, the T helper cell progeny (Th0 cells) then evolve
into Th1 lymphocytes. In this manner, microbial infection in
Figure 1 Functional changes associ-
ated with endothelial cell activation in
atherosclerosis. VCAM-1 indicates vascu-
lar cell adhesion molecule 1; RANTES,
regulated on activation normal T ex-
pressed and secreted chemokine; MCP-1,
monocyte chemoattractant protein 1;
PDGF, platelet-derived growth factor;
TGF-␤, transforming growth factor ␤;
ACE, angiotensin-converting enzyme;
ET-1, endothelin 1; ECE, endothelin-con-
verting enzyme; NO, nitric oxide; PGI2,
prostacyclin; CNP, C-type natriuretic pep-
tide; AM, adrenomedullin; TM, thrombo-
modulin; tPA, tissue-type plasminogen
activator; IL-1, interleukin-1; IL-6, inter-
leukin-6; CSFs, colony-stimulating fac-
tors; COX, cyclooxygenase; SODs, super-
oxide dismutases.
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atherosclerotic plaques can promulgate the underlying disease
even when the major immunogen is oxidized LDL cholesterol.
Cytokine secretion profiles of cloned T cells indicate that up to
81% of lymphocytes in atherosclerotic plaques are of the Th0
phenotype (1), emphasizing the importance of the production of
IL-12 in sustaining a Th1-type immune response in atheroscle-
rotic lesions.
For reasons that are not entirely clear, macrophages and
phagocytic vascular smooth muscle cell phenotypes appear to
be unable to fully digest phagocytosed lipid and are destined
to become lipid-laden “foam” cells. This appears to be related
in part to the fact that their receptors for oxidized LDLs are
not downregulated by lipid ingestion. Hence, there is no
feedback mechanism to regulate the phagocytosis of these
modified lipoproteins. Foam cells eventually die, possibly by
apoptosis (programmed cell death), leaving a complex array
of partially digested lipid to accumulate in the intima of the
vessel wall. Over time, it is this process that leads to the
Volume 29 䡠 Number 2 䡠 April 2001
Figure 2 T-cell activation of macro-
phages in atherosclerosis. TCR indicates
T-cell receptor; IFN-gamma, interferon ␥;
CD4, a coreceptor molecule unique to T
helper cells; MHC, major histocompatibil-
ity complex; VSMC, vascular smooth
muscle cell; ROIs, reactive oxygen inter-
mediates; ox-LDL, oxidized LDL.
formation of the necrotic center in atherosclerotic plaques.
Vascular smooth muscle cells wall off this necrotic center by
producing a cap consisting of a connective tissue matrix
generated under the influence of TGF-␤. Rupture of the cap
exposes platelets to thrombogenic constituents in the core,
resulting in clot formation and possible thromboembolization
and/or occlusion of an already narrowed lumen. It is this
event that precipitates most myocardial infarctions (10).
PHYSICAL ACTIVITY AND ATHEROGENESIS
There is convincing evidence that, along with interven-
tions designed to reduce risk factors such as emotional stress,
hyperlipidemia, hypertension, overweight, and smoking, ex-
ercise training can help to slow, halt, and even reverse the
progression of atherosclerotic coronary artery disease (5).
Whereas the relative contribution of each of these interven-
Figure 3 Macrophage-associated acti-
vation and differentiation of naïve T cells.
B7 indicates a coactivator molecule; IL-2,
inteleukin-2; IL-2R, IL-2 receptor; Th0, a
naïve T helper cell; Th1, a T helper-type 1
cell; IL-12, interleukin-12.
Exercise and Atherogenesis 51
tions is not known, it is well established that exercise training
alone enhances insulin sensitivity, improves glucose toler-
ance, increases HDL cholesterol levels, reduces triglyceride
and LDL cholesterol levels, promotes stress and weight re-
duction, and improves blood pressure levels and cardio-
vascular function. Hence, physical activity reduces the
morbidity and mortality associated with atherosclerotic
heart disease through direct (cardiovascular) and indirect
(risk factor modification) mechanisms, independent of
other interventions.
EXERCISE AND ENDOTHELIAL CELL FUNCTION
Recent studies indicate that exercise also exerts its bene-
ficial effects by improving endothelial cell function and pro-
moting an atheroprotective phenotype.
Hambrecht and associates examined the effects of 4 wk of
exercise training on endothelium-dependent vasodilatation
of coronary vessels in 10 patients with documented coronary
artery disease (8). Compared with a sedentary control group
of 9 patients, exercise training lessened coronary vasocon-
striction and improved blood flow changes in response to
acetylcholine, indicating that coronary endothelial function
had improved in the patients who exercised. Smooth muscle
function in the coronary microvasculature also improved
with exercise training, as indicated by an increase in coronary
blood flow in response to adenosine. Because cholesterol-
lowering therapy and cessation of smoking have also been
shown to improve endothelial cell function in persons with
coronary artery disease (15), it is important to note that the
results in Hambrecht’s study could not be explained on the
basis of risk factor modification.
The authors attribute their findings to exercise-related
changes in hemodynamic stresses placed on the coronary
endothelium of the study subjects. It has long been appreci-
ated that atherosclerosis preferentially involves the outer
edges of vessel bifurcations, areas where the frictional force
acting on the cell surface as a result of blood flow (hemody-
namic shear stress) is weaker than in protected areas. Recent
in vitro studies have identified shear stress as being an im-
portant determinant of endothelial cell function and pheno-
type (15). Normal arterial level shear stress (⬎15 dyne/cm2)
induces endothelial quiescence and an atheroprotective phe-
notype, whereas low shear stress (⬍4 dyne/cm2), which is
prevalent at atherosclerosis-prone sites, stimulates an athero-
genic phenotype in endothelium. Atheroprotective endothe-
lial cells discourage leukocyte adhesion and egress by down-
regulating their expression of adhesion and chemotactic
molecules while performing other beneficial functions, such
as the production of vasodilators, antioxidant enzymes,
growth inhibitors, and anticoagulants. As noted, atherogenic
endothelial cells attract monocytes and T cells by upregulat-
ing their expression of adhesion molecules and chemokines.
They also produce more growth factors, vasoconstrictors,
procoagulants, and inflammatory cytokines than quiescent
endothelial cells (11). In keeping with the in vitro studies on
hemodynamic shear stress, Hambrecht’s findings suggest that
exercise-related increases in shear stress stimulate an athero-
protective phenotype in endothelial cells in vivo. Hambre-
52 Exercise and Sport Sciences Reviews
cht’s findings are in keeping with the results of other studies
in humans and animals showing that regular exercise im-
proves endothelial cell function (11,15).
EXERCISE AND T-CELL FUNCTION
In a study involving 43 subjects at risk of having ischemic
heart disease, Smith and coworkers found that 6 months of
moderate-intensity exercise caused a 58.3% reduction in blood
mononuclear cell production of the atherogenic cytokines
IFN-␥, TNF-␣, and IL-1␤ and a 35.9% increase in the produc-
tion of the atheroprotective cytokines TGF-␤, IL-4, and IL-10
(14). The results were highly significant (P ⬍ 0.001) and could
not be attributed to modification of risk factors during the study
but rather correlated with the total number of hours subjects
spent doing exercises involving repetitive lower-body motion
(cycling, running, walking, skiing, climbing, and aerobic exer-
cises). After the exercise program, changes in cellular function
were reflected systemically by a 35% decrease in serum levels of
C-reactive protein, suggesting that similar functional changes
were occurring in lymphocytes and monocytes infiltrating ath-
erosclerotic lesions.
The authors found that exercise had a particularly signif-
icant attenuating effect on the production of IFN-␥ and
TNF-␣. TNF-␣ is produced primarily by monocytes and
macrophages and is a potent proinflammatory cytokine (3).
IFN-␥ is produced primarily in Th1 cells and is the most
important cytokine regulating the activities of mononuclear
phagocytes (4) and therefore cell-mediated immune re-
sponses of the type seen in atherosclerotic lesions. Both
cytokines can activate endothelial cells, macrophages, and
vascular smooth muscle cells, thereby contributing to leuko-
cyte recruitment, endothelial cell procoagulant activity, LDL
oxidation, and foam cell formation in atherosclerotic lesions
(3). IFN-␥ can also weaken the fibrous cap of atherosclerotic
lesions by inhibiting TGF-␤ production, and TNF-␣ can
induce apoptosis in endothelial and vascular smooth muscle
cells (10). The importance of IFN-␥ in atherogenesis has
been demonstrated in transgenic mice with targeted disrup-
tions of the apoE gene and the IFN-␥ receptor gene (apoE
0/IFN-␥R0 mice) (7). These mice demonstrate a substantial
reduction in atherosclerotic lesion size, cellularity, and lipid
accumulation and an increase in plasma concentrations of
potentially atheroprotective phospholipid/apoA-IV–rich
particles compared with apoE 0 mice, suggesting that IFN-␥
promotes and modifies atherosclerosis through its local ef-
fects in the arterial wall as well as by its effects on plasma
lipoproteins. It is important to note that IFN-␥ has been
shown to be the dominant cytokine in up to 98% of T-cell
clones isolated from atherosclerotic plaques (1).
In contrast to the atherogenic cytokines, the production of
atheroprotective cytokines was augmented by exercise. These
cytokines are produced in T helper type 2 (Th2) cells (IL-4
and IL-10) and T helper type 3 (Th3) cells (TGF-␤1). They
inhibit cell-mediated immune reactions of the type seen in
atherosclerotic lesions, primarily by suppressing macrophage
and Th1 lymphocyte function (3). This is achieved by down-
regulation of the production of IL-1, TNF-␣, and IL-12 by
monocytes and macrophages (IL-4, IL-10, and TGF-␤) and
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IFN-␥ production by Th1 lymphocytes (IL-10 and TGF-␤).
Interleukin-4 also inhibits the development of Th1 cells
while promoting the development of Th2 and Th3 cells.
Furthermore, TGF-␤ helps prevent exposure of the necrotic
core of atherosclerotic plaques by stimulating vascular
smooth muscle cells to produce a fibrous cap. This cytokine
also inhibits the proliferation and migration of vascular
smooth muscle cells into the intima, another atheroprotec-
tive activity (10).
This study indicates that long-term exercise training sig-
nificantly increases the proportion of circulating T cells with
atheroprotective properties and supports the probability that
similar phenotypic changes are occurring in mononuclear
cells infiltrating atherosclerotic lesions.
ENDOTHELIUM AND T CELLS: A QUID PRO QUO
RELATIONSHIP
It would appear that, in persons with proven or suspected
coronary atherosclerosis, exercise training stimulates an
atheroprotective phenotype in both endothelial cells and T
cells (Figure 4). It also seems that in atherogenesis, endothe-
lial and T cells have a quid pro quo relationship. For example,
the atheroprotective T cell cytokines IL-4, IL-10, and TGF-␤
inhibit endothelial cell activation and apoptosis by suppress-
ing the production of IL-1 and TNF-␣ by macrophages. In
turn, the healthy endothelium, by restricting its expression of
molecules that invite the influx of atherogenic T cells and
monocytes and by producing TGF-␤, minimizes the produc-
tion of cytokines that inhibit the development of atheropro-
tective T cells from Th0 progenitors (IFN-␥ and IL-12). A
similar relationship appears to exist between atherogenic
endothelial and T cells. Atherogenic endothelial phenotypes
express adhesion molecules and produce chemokines that
favor egress of Th1 cells and monocytes, while these athero-
genic mononuclear cells return the favor by producing cyto-
kines that further activate the endothelium. Hence, once an
Volume 29 䡠 Number 2 䡠 April 2001
Figure 4 Functional characteristics and
interrelationships between atheroprotec-
tive endothelial cell (APEC) and T cell
(APTC) phenotypes, and atherogenic en-
dothelial cell (AGEC) and T cell (AGTC)
phenotypes. NO indicates nitric oxide;
PGI2, prostacyclin; CNP, C-type natri-
uretic peptide; tPA, tissue-type plasmino-
gen activator; COX-1,2, cyclooxygenases 1
and 2; SODs, superoxide dismutases;
TGF-␤, transforming growth factor ␤;
PDGF-␤, platelet-derived growth factor-␤;
ACE, angiotensin-converting enzyme;
ET-1, endothelin 1; ECE, endothelin-con-
verting enzyme; TM, thrombomodulin;
VCAM-1, vascular cell adhesion molecule
1; MCP-1, monocyte chemoattractant pro-
tein 1; IL-2, interleukin-2; IL-10, interleukin-
10; IL-4, interleukin-4; IFN-␥, interferon-␥;
TNF-␣, tumor necrosis factor-␣; IL-1, inter-
leukin-1; IL-12, interleukin-12.
atherogenic or atheroprotective process is initiated, it tends
to be self-sustaining.
References
1. de Boer, O.J., A.C. van der Wal, C.E. Verhagen, and A.E. Becker.
Cytokine secretion profiles of cloned T cells from human aortic ath-
erosclerotic plaques. J. Pathol. 188:174 –179, 1999.
2. Blair, S.N., J.B. Kampert, H.W. Kohl III, et al. Influences of cardiore-
spiratory fitness and other precursors on cardiovascular disease and
all-cause mortality in men and women. JAMA. 276:205–210, 1996.
3. Borish, L., and L.J. Rosenwasser. Update on cytokines. J. Allergy Clin.
Immunol. 97:719 –733, 1996.
4. Farrar, M.A., and R.D. Schreiber. The molecular cell biology of inter-
feron-␥ and its receptor. Annu. Rev. Immunol. 11:571– 611, 1993.
5. Franklin, B.A., and J.K. Khan. Delayed progression or regression of
coronary atherosclerosis with intensive risk factor modification: effects
of diet, drugs, and exercise. Sports Med. 22:306 –320, 1996.
6. Frostegard, J., A.K. Ulfgren, P. Nyberg, et al. Cytokine expression in
advanced human atherosclerotic plaques: dominance of pro-inflamma-
tory (Th1) and macrophage-stimulating cytokines. Atherosclerosis. 145:
33– 43, 1999.
7. Gupta, S., A.M. Pablo, Xc. Jiang, N. Wang, A.R. Tall, and C. Schindler.
IFN-gamma potentiates atherosclerosis in apoE knock-out mice. J. Clin.
Invest. 99:2752–2761, 1997.
8. Hambrecht, R., A. Wolf, S. Gielen, et al. Effect of exercise on coronary
endothelial function in patients with coronary artery disease. N. Engl.
J. Med. 342:454 – 460, 2000.
9. Labarrere, C.A., D.R. Nelson, and W.P. Faulk. Endothelial activation
and development of coronary artery disease in transplanted human
hearts. JAMA. 278:1169 –1175, 1997.
10. Libby, P. Changing concepts of atherogenesis. J. Intern. Med. 247:349 –
358, 2000.
11. Malek, A.M., S.L. Alper, and S. Izumo. Hemodynamic shear stress and
its role in atherosclerosis. JAMA. 282:2035–2042, 1999.
12. Mortality patterns: preliminary data, United States. MMWR Morb.
Mortal. Wkly. Rep. 46:941–944, 1997.
13. NIH Consensus Development Panel on Physical Activity and Cardio-
vascular Health. Physical activity and cardiovascular health. JAMA.
276:241–246, 1996.
14. Smith, J.K., R. Dykes, J.E. Douglas, G. Krishnaswamy, and S. Berk.
Long-term exercise and atherogenic activity of blood mononuclear cells
in persons at risk of developing ischemic heart disease. JAMA. 281:
1722–1727, 1999.
15. Vita, J.A., and J.F. Keaney Jr. Exercise: toning up the endothelium.
N. Engl. J. Med. 342:503–504, 2000.
Exercise and Atherogenesis 53