Exercise and Atherogenesis : Exercise and Sport Sciences Reviews (original) (raw)
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 evidence 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 understood, although it is probably multifactorial. Risk factors such as hypertension, obesity, hyperlipidemia, and insulin resistance may respond favorably to moderate levels of physical 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 favorably influence the course of atherogenesis in ways yet to be discovered. Whatever the reasons, reports have documented a strong and independent association of low cardiorespiratory 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 immunologically mediated inflammatory disease (10). Atherosclerotic 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-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor-β (TGF-β). 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 endothelial 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 protein, 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-α, 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 phagocytes, 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 endothelial cells are thought to be activated in response to the injurious effects of toxic lipids, abnormally high or low hemodynamic shear forces, infection with agents such as Chlamydia 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 stimulates the growth of vascular smooth muscle cells by increasing its production of growth factors while decreasing its production of TGF-β, 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 minimizing 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 endothelial and vascular smooth muscle cell activation (IL-1), acute-phase protein production (IL-6), and granulopoiesis (colony-stimulating factors). Finally, endothelial cell production 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).
Functional changes associated with endothelial cell activation in atherosclerosis. VCAM-1 indicates vascular cell adhesion molecule 1; RANTES, regulated on activation normal T expressed and secreted chemokine; MCP-1, monocyte chemoattractant protein 1; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β; ACE, angiotensin-converting enzyme; ET-1, endothelin 1; ECE, endothelin-converting enzyme; NO, nitric oxide; PGI2, prostacyclin; CNP, C-type natriuretic peptide; AM, adrenomedullin; TM, thrombomodulin; tPA, tissue-type plasminogen activator; IL-1, interleukin-1; IL-6, interleukin-6; CSFs, colony-stimulating factors; COX, cyclooxygenase; SODs, superoxide dismutases.
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 histocompatibility 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-γ, a potent atherogenic cytokine, and by binding to CD40 ligands present on the macrophages’ cellular membranes. Once activated, macrophages are more efficient in ingesting, processing, and presenting antigens, including other suspect atherogenic immunogens such as HSP 60 and infectious agents, to Th1 cells. They also secrete increased amounts of proinflammatory cytokines (TNF-α, 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).
T-cell activation of macrophages in atherosclerosis. TCR indicates T-cell receptor; IFN-gamma, interferon γ; CD4, a coreceptor molecule unique to T helper cells; MHC, major histocompatibility complex; VSMC, vascular smooth muscle cell; ROIs, reactive oxygen intermediates; ox-LDL, oxidized LDL.
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 conjunction 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 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 atherosclerotic lesions.
Macrophage-associated activation 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.
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 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-β. 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 interventions designed to reduce risk factors such as emotional stress, hyperlipidemia, hypertension, overweight, and smoking, exercise 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 interventions is not known, it is well established that exercise training alone enhances insulin sensitivity, improves glucose tolerance, increases HDL cholesterol levels, reduces triglyceride and LDL cholesterol levels, promotes stress and weight reduction, and improves blood pressure levels and cardiovascular 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 beneficial effects by improving endothelial cell function and promoting 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 vasoconstriction 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 appreciated 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 (hemodynamic shear stress) is weaker than in protected areas. Recent in vitro studies have identified shear stress as being an important determinant of endothelial cell function and phenotype (15). Normal arterial level shear stress (>15 dyne/cm2) induces endothelial quiescence and an atheroprotective phenotype, whereas low shear stress (<4 dyne/cm2), which is prevalent at atherosclerosis-prone sites, stimulates an atherogenic phenotype in endothelium. Atheroprotective endothelial cells discourage leukocyte adhesion and egress by downregulating 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 upregulating 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 atheroprotective phenotype in endothelial cells in vivo. Hambrecht’s findings are in keeping with the results of other studies in humans and animals showing that regular exercise improves 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-γ, TNF-α, and IL-1β and a 35.9% increase in the production of the atheroprotective cytokines TGF-β, 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 exercises). 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 atherosclerotic lesions.
The authors found that exercise had a particularly significant attenuating effect on the production of IFN-γ and TNF-α. TNF-α is produced primarily by monocytes and macrophages and is a potent proinflammatory cytokine (3). IFN-γ is produced primarily in Th1 cells and is the most important cytokine regulating the activities of mononuclear phagocytes (4) and therefore cell-mediated immune responses of the type seen in atherosclerotic lesions. Both cytokines can activate endothelial cells, macrophages, and vascular smooth muscle cells, thereby contributing to leukocyte recruitment, endothelial cell procoagulant activity, LDL oxidation, and foam cell formation in atherosclerotic lesions (3). IFN-γ can also weaken the fibrous cap of atherosclerotic lesions by inhibiting TGF-β production, and TNF-α can induce apoptosis in endothelial and vascular smooth muscle cells (10). The importance of IFN-γ in atherogenesis has been demonstrated in transgenic mice with targeted disruptions of the apoE gene and the IFN-γ receptor gene (apoE 0/IFN-γR0 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-γ promotes and modifies atherosclerosis through its local effects in the arterial wall as well as by its effects on plasma lipoproteins. It is important to note that IFN-γ 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-β1). 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 downregulation of the production of IL-1, TNF-α, and IL-12 by monocytes and macrophages (IL-4, IL-10, and TGF-β) and IFN-γ production by Th1 lymphocytes (IL-10 and TGF-β). Interleukin-4 also inhibits the development of Th1 cells while promoting the development of Th2 and Th3 cells. Furthermore, TGF-β 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 atheroprotective activity (10).
This study indicates that long-term exercise training significantly 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, endothelial and T cells have a quid pro quo relationship. For example, the atheroprotective T cell cytokines IL-4, IL-10, and TGF-β inhibit endothelial cell activation and apoptosis by suppressing the production of IL-1 and TNF-α 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-β, minimizes the production of cytokines that inhibit the development of atheroprotective T cells from Th0 progenitors (IFN-γ 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 atherogenic mononuclear cells return the favor by producing cytokines that further activate the endothelium. Hence, once an atherogenic or atheroprotective process is initiated, it tends to be self-sustaining.
Functional characteristics and interrelationships between atheroprotective endothelial cell (APEC) and T cell (APTC) phenotypes, and atherogenic endothelial cell (AGEC) and T cell (AGTC) phenotypes. NO indicates nitric oxide; PGI2, prostacyclin; CNP, C-type natriuretic peptide; tPA, tissue-type plasminogen activator; COX-1,2, cyclooxygenases 1 and 2; SODs, superoxide dismutases; TGF-β, transforming growth factor β; PDGF-β, platelet-derived growth factor-β; ACE, angiotensin-converting enzyme; ET-1, endothelin 1; ECE, endothelin-converting enzyme; TM, thrombomodulin; VCAM-1, vascular cell adhesion molecule 1; MCP-1, monocyte chemoattractant protein 1; IL-2, interleukin-2; IL-10, interleukin-10; IL-4, interleukin-4; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; IL-1, interleukin-1; IL-12, interleukin-12.
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Keywords:
T cells; cytokines; endothelium
© 2001 American College of Sports Medicine