EDITORIAL COMMENT
The Paradox of Hypoxic and Oxidative Stress in Atherosclerosis*
Manuel Mayr, MD, PhD*,
Anissa Sidibe, MSc and
Anna Zampetaki, PhD
Cardiovascular Division, King’s College, London, United Kingdom.
* Reprint requests and correspondence: Dr. Manuel Mayr, Cardiovascular Division, King’s College, 125 Coldharbour Lane, SE5 9NU, London, United Kingdom. (Email: manuel.mayr{at}kcl.ac.uk).
In this issue of the Journal, Sluimer et al. (1) demonstrate the presence of hypoxia in human atherosclerotic lesions. The pimonidazole technique has been widely employed to detect hypoxia in solid tumors, but the hypoxic state of the human arterial tissue in vivo has not been investigated so far. Although other factors like inflammation (2) and oxidized lipoproteins (3) can induce responses similar to hypoxia (i.e., the expression of hypoxia-inducible factor [HIF]-1 and HIF-related target genes play a pivotal role in the survival of macrophages in an inflammatory microenvironment, mainly through the regulation of the glycolytic pathway), the observed relationship between hypoxia, macrophage content, and microvessel density suggests a potential role for hypoxic macrophages in plaque angiogenesis.
Hypoxia in atherosclerosis.
Hypoxia in the arterial wall has for many years been implicated in the development of atherosclerosis, and the presence of hypoxic regions has been extensively demonstrated in animal lesions (4–7). In rabbits, normal aortas and early lesions were not hypoxic and had homogenous concentrations of energy metabolites. In advanced plaques, however, the cores were characterized by hypoxia, low concentrations of adenosine triphosphate (ATP), glucose, and glycogen but a high concentration of lactate. In particular, the majority of ATP-depleted macrophages within the core were viable but severely hypoxic (6). The findings by Sluimer et al. (1) are in line with these animal experiments: hypoxia in human atherosclerosis was strong in macrophage clusters surrounding the plaque core, but absent in a 100- to 250-µm rim bordering the lumen, illustrating that hypoxia results from a combination of decreased oxygen supply and increased oxygen demand.
Oxygen mass transport versus hemodynamics.
Oxygen moves down the pressure gradient (pO2) from a relatively high level in the arterial blood to the cell by diffusion. The maximum diffusion distance for oxygen within tissues is generally given as 300 µm. Based on the fact that zones of hypoxia tend to colocalize with areas of atherosclerotic lesions, certain models have suggested that abnormal mass transport of oxygen may promote atherosclerosis. However, the interpretation is complicated by the fact that these zones tend to have abnormal shear stress patterns, which are also atherogenic. To date, it is still not clear how to separate the 2 effects. Flow separation on the outer wall of the sinus provides a very strong fluid mechanical barrier to oxygen transport; whereas at the inner wall of the sinus, the mechanism of transport is controlled by the wall consumption rate (8). For example, the geometric features and associated hemodynamic features of the carotid bifurcation alter oxygen mass transport, leading to a region of hypoxia that may contribute to the localization of atherosclerosis on the outer wall of the carotid sinus. In addition, the pulsatile nature of flow affects oxygen mass transport.
Oxygen supply versus demand.
Using the most basic homogenous, 1-dimensional models for oxygen transport in vascular tissue, one can show a link between the progression of atherosclerosis and oxygen transport (Fig. 1). In such a model, it can be assumed that the physical properties governing this process are the oxygen consumption rate and the oxygen transmissibility (diffusion-convection product, Dk). Taking this into account, at the onset of the atherosclerosis process, subintimal thickening may generate hypoxic sites as a result of increased diffusion distances (reduction in Dk) or from elevated oxygen consumption. The observations by Sluimer et al. (1)—that staining for hypoxia is scarce in early atherosclerotic lesions and restricted to very few cells in the inner wall layer—describe a scenario, where though the level of oxygenation is low, it is still adequate to maintain cellular processes. In advanced atherosclerosis, however, the increased size of the neointima and lipid accumulation further reduces the area that can be maintained viable by diffusion, and the adventitial vasa vasorum fails to deliver sufficient oxygen and solutes to the arterial wall. Adenosine triphosphate-depleted zones were seen deep in the pig media and in rabbit plaques even at high oxygen and glucose concentrations, confirming insufficient diffusion of oxygen but also of other metabolites in the arterial wall (5). Similarly, our combined proteomic and metabolomic analysis of aortas from apolipoprotein E–deficient mice revealed a coordinated decline of energy metabolites even before lesion development (10). Thus, decreased supply in combination with increased demand impairs the energy metabolic steady state in atherosclerosis, and elevated oxygen consumption determines the location of severely hypoxic zones in advanced lesions.
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Figure 1 Regions of Curvature and Bifurcations in Arteries Have Abnormal Mass Transport of Oxygen (Low pO2)
During atherogenesis, subintimal thickening increases the diffusion distances and therefore reduces oxygen transmobility (Dk). In advanced lesions, the diffusion capacity is impaired at the same time; oxygen consumption (Q) is augmented by increased accumulation of inflammatory cells and foam cells creating areas of hypoxia. Plaque angiogenesis may be an adaptive mechanism to counteract hypoxia, but it can promote plaque rupture. Adapted from Ethier et al. (9).
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Hypoxia versus oxidative stress.
Macrophages are known to have a higher glycolytic turnover compared with other vascular cell types (i.e., smooth muscle cells) and foam cells, in particular, consume high amounts of oxygen and glucose (4,6). The latter is consistent with the findings by Sluimer et al. (1) that macrophages were the predominant cell type positive for the hypoxia marker pimonidazol in human atherosclerosis. Pimonidazole is a 2-nitroimidazole containing a basic, piperidine moiety. It is widely considered to be a hypoxia-specific dye, as it is reduced in cells with low oxygen tension. The resulting pimonidazole derivatives form protein adducts, which can be detected by immunostaining. Although pimonidazole itself may react with reactive oxygen species (ROS), the antipimonidazole antibody only recognizes hypoxia derivatives. To rule out that the staining with pimonidazol was influenced by ROS, the authors performed an in vitro experiment with hydrogen peroxide. While this is some reassurance that the staining pattern is not directly influenced by free radicals, areas of pimonidazole staining probably colocalize with oxidative stress in atherosclerosis. At a first glance, increased ROS seem counterintuitive in macrophages with limited oxygen concentrations. However, one of the emerging complexities in free-radical biology is that superoxide generation can be elevated in response to both high and low levels of oxygen (11). During hypoxia, mitochondrial electron transport slows, augmenting the reduction state of electron carriers. This accumulation of reducing equivalents favors superoxide production at low oxygen concentrations by increasing the electrical potential for single electron reduction of oxygen to superoxide (12). Notably, ROS as well as hypoxia have been demonstrated to facilitate the conversion of human macrophages into foam cells (13,14). Although the concept of "reductive stress" may help to reconcile the paradox of oxidative and hypoxic stress in atherosclerosis, it requires confirmation in future mechanistic studies.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Sluimer JC, Gasc J-M, van Wanroij JL, et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis J Am Coll Cardiol 2008;51:1258-1265.[Abstract/Free Full Text]2. Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation Cell 2003;112:645-657.[CrossRef][Web of Science][Medline] 3. Shatrov VA, Sumbayev VV, Zhou J, Brune B. Oxidized low-density lipoprotein (oxLDL) triggers hypoxia-inducible factor-1alpha (HIF-1alpha) accumulation via redox-dependent mechanisms Blood 2003;101:4847-4849.[Abstract/Free Full Text] 4. Bjornheden T, Levin M, Evaldsson M, Wiklund O. Evidence of hypoxic areas within the arterial wall in vivo Arterioscler Thromb Vasc Biol 1999;19:870-876.[Abstract/Free Full Text] 5. Levin M, Bjornheden T, Evaldsson M, Walenta S, Wiklund O. A bioluminescence method for the mapping of local ATP concentrations within the arterial wall, with potential to assess the in vivo situation Arterioscler Thromb Vasc Biol 1999;19:950-958.[Abstract/Free Full Text] 6. Leppanen O, Bjornheden T, Evaldsson M, Boren J, Wiklund O, Levin M. ATP depletion in macrophages in the core of advanced rabbit atherosclerotic plaques in vivo Atherosclerosis 2006;188:323-330.[CrossRef][Medline] 7. Heughan C, Niinikoski J, Hunt TK. Oxygen tensions in lesions of experimental atherosclerosis of rabbits Atherosclerosis 1973;17:361-367.[CrossRef][Medline] 8. Tada S, Tarbell JM. Oxygen mass transport in a compliant carotid bifurcation model Ann Biomed Eng 2006;34:1389-1399.[CrossRef][Web of Science][Medline] 9. Ethier CR. Computational modeling of mass transfer and links to atherosclerosis Ann Biomed Eng 2002;30:461-471.[CrossRef][Web of Science][Medline] 10. Mayr M, Chung YL, Mayr U, et al. Proteomic and metabolomic analyses of atherosclerotic vessels from apolipoprotein E-deficient mice reveal alterations in inflammation, oxidative stress, and energy metabolism Arterioscler Thromb Vasc Biol 2005;25:2135-2142.[Abstract/Free Full Text] 11. Clanton TL. Hypoxia-induced reactive oxygen species formation in skeletal muscle J Appl Physiol 2007;102:2379-2388.[Abstract/Free Full Text] 12. Misra HP, Fridovich I. The univalent reduction of oxygen by reduced flavins and quinones J Biol Chem 1972;247:188-192.[Abstract/Free Full Text] 13. Aviram M. Macrophage foam cell formation during early atherogenesis is determined by the balance between pro-oxidants and anti-oxidants in arterial cells and blood lipoproteins Antioxid Redox Signal 1999;1:585-594.[Medline] 14. Bostrom P, Magnusson B, Svensson PA, et al. Hypoxia converts human macrophages into triglyceride-loaded foam cells Arterioscler Thromb Vasc Biol 2006;26:1871-1876.[Abstract/Free Full Text]
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