European Heart Journal Advance Access originally published online on July 30, 2008
European Heart Journal 2008 29(18):2317-2318; doi:10.1093/eurheartj/ehn350
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Leucocyte activation in coronary heart disease: but how and why?
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Leucocytosis, a marker of inflammation, is associated with a greater cardiovascular risk. Thus, leucocyte myeloperoxidase (MPO) could serve as a biomarker of cardiovascular diseases, as shown by Morrow et al.1 But, they did not study as to why and how leucocyte activation occurs in coronary heart disease (CHD).
Infiltration of intima by leucocytes and macrophages is an early event to occur in atherosclerosis. Elevated low-density lipoprotein (LDL), hypertension, hyperglycaemia, and other systemic factors initiate and accelerate atherosclerosis. Despite the fact that the entire vascular endothelium is exposed to these systemic factors, atherosclerotic lesions occur in a patchy manner and develop preferentially at bifurcations, branch points, and inner curvatures of arteries, suggesting that local factors play a major role in the development of atherosclerosis. Haemodynamic forces induce the expression of pro- inflammatory genes2 that initiate and accelerate atherosclerosis at these points of shear stress. Normocholesterolemic C57BL/6 mice and rabbits showed activation of NF-
B and elevated expression of VCAM-1 and ICAM-1, upregulation of pro-inflammatory genes IL-1, IL-6, MCP-1, as well as antioxidant genes glutathione peroxidase and glutathione-S-transferase in endothelial cells in atherosclerosis-susceptible regions of the ascending aorta.3 Intimal accumulation of LDL and its oxidation products preceded monocyte recruitment into early atherosclerotic lesions, suggesting that lipid accumulation triggers inflammatory response characterized by upregulation of the expression of chemokines and adhesion molecules in the lesion-prone areas in the intima that contributes to leucocyte accumulation and atherosclerotic lesion formation.3
Healthy endothelial cells prevent excess expression of adhesion molecules, resist increases in LDL and cholesterol transport and retention, and abrogate the activation of NF-B and the induction of expression of pro- inflammatory genes induced by haemodynamic forces at atherosclerosis-prone regions by producing factors that counter pro-atherosclerotic events. The patchy nature of atherosclerosis suggests that arterial walls undergo regional disturbances of metabolism that include the uncoupling of respiration and oxidative phosphorylation, which may be characteristic of blood vessels being predisposed to the development of atherosclerosis.4,5 Oxidative stress and abnormalities of uncoupling proteins produce smooth muscle contraction and cause hypertension, and respiratory uncoupling is increased in the aortae of experimental animals that are susceptible to atherosclerosis.5 Bernal-Mizrachi et al.6 showed that UCP-1 expression in aortic smooth muscle cells causes hypertension and increases atherosclerosis without affecting the cholesterol levels. This increase in UCP-1 expression enhanced superoxide anion production and decreased the availability of nitric oxide, suggesting that oxidative stress has been elevated. Thus, inefficient metabolism in blood vessels causes atherosclerosis.
One of the earliest signs of atherosclerosis is the development of abnormal mitochondria in smooth muscle cells. Arteries have marginal oxygenation, and hypoxia reduces the respiratory control ratio.3 Uncoupled respiration precedes atherosclerosis at lesion-prone sites but not at the sites that are resistant to atherosclerosis.5 Disease-free aortae have abundant concentrations of the essential fatty acid (EFA)-linoleate (LA), whereas fatty streaks are deficient in EFAs.5 EFA deficiency promotes respiratory uncoupling7 and atherosclerosis8. Hence, local disturbances of EFA metabolism in the arterial wall could be responsible for atherosclerosis and vascular disease.
EFAs-linoleic acid (LA; 18:2 
-6) and 
-linolenic acid (18:3 -3) give rise to lipoxins (LXs), resolvins, and protectins in addition to forming precursors to various eicosanoids (reviewed in 3). Aspirin converts arachidonic acid (20:4 -6), eicosapentaenoic acid (20:5 -3), and docosahexaenoic acid (22:6 -3) to form aspirin-triggered 15 epimer LXs (ATLs) that inhibit inflammation3 on the vessel wall by regulating the motility of polymorphonuclear leucocytes (PMNs), eosinophils, and monocytes. LXs deficiency leads to an interaction between PMN and endothelial cells that result in endothelial damage, initiation, and progression of atherosclerosis. LXs, resolvins, and protectins inhibit cytokine generation, leucocyte recruitment, leucocyte diapedesis, and exudate formation, and suppress the production of pro-inflammatory cytokines. Hence, the local deficiency of LXs, resolvins, and NPD1 could initiate atheroslcerosis. Furthermore, lipoxins suppress the production of MPO from activated leucocytes.3,9 Increased generation of MPO by leucocytes could be an indication of decreased formation of lipoxins, resolvins, and protectins by endothelial cells. This implies that enhancing the formation of endothelial LXs, resolvins, and protectins may suppress leucocyte activation and MPO generation, and prevent CHD.
References
- Morrow DA, Sabatine MS, Brennan M-L, de Lemos JA, Murphy SA, Ruff CT, Rifai N, Cannon CP, Hazen SL. Concurrent evaluation of novel cardiac biomarkers in acute coronary syndrome: myeloperoxidase and soluble CD40 ligand and the risk of recurrent ischaemic events in TACTICS-TIMI 18. Eur Heart J (2008) 29:1096–1102.
[Abstract/Free Full Text] - Brooks AR, Lelkes PI, Rubanyi GM. Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow. Physiol Genomics (2002) 9:27–41.
[Abstract/Free Full Text] - Das UN. A defect in the activity of
6 and 5 desaturases may be a factor in the initiation and progression of atherosclerosis. Prostaglandins Leukot Essen Fatty Acids (2007) 76:251–268.[CrossRef][Web of Science][Medline] - Jongstra-Bilen J, Haidari M, Zhu SN, Chen M, Guha D, Cybulsky MI. Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis. J Exp Med (2006) 203:2073–2083.
[Abstract/Free Full Text] - Santerre RF, Nicolosi RJ, Smith SC. Respiratory control in preatherosclerotic susceptible and resistant pigeon aortas. Exp Mol Pathol (1974) 20:397–406.[CrossRef][Web of Science][Medline]
- Bernal-Mizrachi C, Gates AC, Weng S, Imamura T, Knutsen RH, DeSantis P, Coleman T, Townsend RR, Muglia LJ, Semenkovich CF. Vascular respiratory uncoupling increases blood pressure and atherosclerosis. Nature (2006) 435:502–506.[CrossRef][Web of Science]
- Hayashida T, Portman OW. Swelling of liver mitochondria from rats fed diets deficient in essential fatty acids. Proc Soc Exp Biol Med (1960) 103:656–659.[CrossRef][Medline]
- Cornwell DG, Panganamala RV. Atherosclerosis an intracellular deficiency in essential fatty acids. Prog Lipid Res (1981) 20:365–376.[CrossRef][Medline]
- Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN. Aspirin-triggered 15-epi-lipoxin A4 and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. J Exp Med (1997) 185:1693–1704.
[Abstract/Free Full Text]
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