Oxidative stress and coronary plaque stability.

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 22, No. 11Oxidative Stress and Coronary Plaque Stability Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBOxidative Stress and Coronary Plaque Stability Keith M. Channon Keith M. ChannonKeith M. Channon From the Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. Search for more papers by this author Originally published1 Nov 2002https://doi.org/10.1161/01.ATV.0000042203.08210.17Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1751–1752Increased production of reactive oxygen species (ROS) in the vascular wall is a characteristic feature of disease states, including atherosclerosis, diabetes and hypertension. ROS, such as superoxide, reduce nitric oxide bioactivity by scavenging and cause oxidation of lipids and target proteins. In addition, recent work has revealed that ROS mediate a wide range of pathological processes in the endothelium, smooth muscle cells, and inflammatory cells.1 ROS are generated by enzyme systems present in cells in the vascular wall, including NAD(P)H oxidase, xanthine oxidase, and nitric oxide synthase. The activities and levels of these enzyme systems are increased in association with vascular disease risk factors2 and in vascular disease states in which oxidative stress is prominent, for example, in diabetes3 and atherosclerosis.See page 1838The NAD(P)H oxidases appear to be particularly important sources of ROS production in blood vessels,4 where they are constitutively active, producing relatively low levels of ROS under basal conditions, but generating higher levels of oxidants in response to stimuli such as growth factors and cytokines. These factors are consistent with a role for nonphagocytic NAD(P)H oxidases in cellular signaling rather than the high-level burst activity characteristic of the phagocyte NAD(P)H oxidase. The NAD(P)H oxidases are multimeric enzymes composed of plasma membrane associated–proteins as well as cytosolic factors. In the phagocytic-type NAD(P)H oxidase, the plasma membrane–associated proteins gp91phox and p22phox compose the flavocytochrome b558 complex, which forms the catalytic subunit of the oxidase. The cytosolic subunits, including p47phox, p67phox, and the G-protein Rac, provide regulatory function.Azumi and colleagues,5 in this issue of Arteriosclerosis, Thrombosis and Vascular Biology, have made important additions to our understanding of the role of ROS in human coronary artery disease. They studied directional coronary atherectomy (DCA) specimens taken from 36 patients with stable or unstable angina pectoris undergoing percutaneous coronary intervention. The cellular composition of these plaque fragments was examined by using immunofluorescence and related to the magnitude and cellular sources of ROS production, visualized by using the superoxide-sensitive fluorescent probe, dihydroethidium (DHE). They report that both ROS production and the presence of oxidized LDL (Ox-LDL) are spatially associated with the p22phox subunit of the NAD(P)H oxidase, directly implicating this enzyme system in ROS generation and oxidative modification of target molecules in human coronary plaques. Indeed, in earlier work, Azumi et al6 showed that total p22phox protein levels were increased in atherosclerotic coronary arteries. In the current study, they now demonstrate that these markers of ROS production were markedly increased in macrophage-rich plaques, that were more likely to originate from patients presenting with unstable rather than stable angina pectoris. Plaques from patients with stable angina tended to have lower ROS production, fewer macrophages and a greater proportion of smooth muscle cells. However, unstable plaques that contained a substantial proportion of smooth muscle cells also showed an additional increase in ROS production in these cells, suggesting up-regulation of ROS production in both smooth muscle cells (SMCs) and macrophages in unstable plaques. These observations are supported by studies of atherosclerotic lesions from human aorta,7 where activated intimal SMCs (but not medial SMCs) and macrophages expressed high levels of NAD(P)H oxidase subunits, and this increase was most striking in macrophage-derived foam cells.These findings are important because they extend our understanding of the biology of plaque stability versus instability and suggest that ROS production in human coronary artery plaques may play a role in regulating plaque stability and in mediating the occurrence of acute coronary syndromes. What are the potential mechanisms that relate ROS production to plaque stability? At the very least, increased ROS production appears to be a marker of unstable plaques, due to the higher proportion of active macrophages present in these lesions. However, several other biologically plausible mechanisms suggest that ROS production may play more direct roles in modulating plaque stability. Superoxide, and peroxynitrite formed by the interaction between superoxide and nitric oxide, are proinflammatory radicals, leading to activation of redox-sensitive transcription factors such as nuclear factor κB and activating protein-1 in endothelial and SMCs, and in macrophages. Superoxide induces expression of matrix-degrading proteases, including MMP-2 and MMP-9 in foam cells that directly contribute to plaque instability.8 The observation by Azumi et al5 of increased Ox-LDL immunofluorescence in association with DHE fluorescence underscores that ROS production promotes formation of Ox-LDL, allowing macrophage scavenger receptor-mediated uptake of Ox-LDL, leading to activated foam cell formation. Ox-LDL has additional effects on smooth muscle and endothelial cell apoptosis that could lead to endothelial erosion and loss of SMCs, increasing plaque vulnerability.The interesting observation of increased ROS production in smooth muscle cells in plaques from patients with unstable angina raises new questions about the role of ROS signaling in SMC biology in the atherosclerotic plaque. The unstable, lipid-rich plaque is characterized by a proportionately lower SMC component and increased SMC apoptosis. In contrast, fibrocellular lesions or the intimal response to balloon or stent injury are SMC-rich, causing luminal stenosis but not acute events related to lesion instability. However, SMC phenotype is an important additional consideration. Activated, “de-differentiated” SMCs produce more superoxide and express higher levels of NAD(P)H oxidase components.9 Correspondingly, NAD(P)H oxidase-derived ROS play important roles in SMC proliferation. Cytokines such as IFN and growth factors, implicated in modulating plaque stability, have marked effects on NAD(P)H oxidase subunit expression and ROS production. Furthermore, the recent identification of SMC homologs of gp91phox (Nox2), Nox1 and Nox4, points to increased complexity of NAD(P)H oxidase regulation in SMCs. Increased or decreased Nox1 expression directly alters cell proliferation in culture, and treatment of SMCs with angiotensin II upregulates Nox1 while downregulating Nox4, suggesting reciprocal regulation of these proteins in relation to SMC growth.10 After arterial balloon injury in the rat, increased superoxide production coincides with activated SMCs and fibroblasts, in association with intimal hyperplasia.11 Interestingly, expression of Nox1, gp91phox, and p22phox is elevated early after balloon denudation, suggesting that NAD(P)H oxidase activity is rapidly induced after vascular injury in vivo, in both SMCs and fibroblasts. In contrast, Nox4 expression increases later after balloon injury, coinciding with a marked reduction in the rate of SMC proliferation. Upregulation of Nox4 in the arterial wall in vivo could attenuate SMC proliferation after vascular injury, thus limiting the “repair” response and may also contribute to induction of apoptosis of neointimal cells that is observed late after balloon injury. Thus, regulation of both ROS production and the expression of NAD(P)H oxidase components is directly relevant to the biological role of SMCs in determining plaque stability versus instability.In human coronary artery segments retrieved from cardiac transplant recipients, Sorescu et al12 also observed striking increases in both ROS production and NAD(P)H oxidase subunits p22phox and gp91phox (Nox2) expression in association with increasing severity of atherosclerotic plaque. The presence of Nox2 was strongly associated with plaque macrophage content, whereas Nox4 was associated with SMCs and was most abundant in advanced fibrocellular plaques, but not in complex plaques with features of instability. Most interestingly for plaque stability, the shoulder region of plaques was a particularly intense area of ROS production, in association with p22phox and Nox2 expression, implicating NAD(P)H oxidase-derived ROS in plaque rupture. A plausible mechanistic link with plaque stability is supported by the observation that HMG CoA-reductase inhibitors (statins), known to stabilize plaques and reduce plaque events, have direct effects on NAD(P)H oxidase activity through inhibition of the Rac G-protein involved enzyme activation.13The important new observations of Azumi et al,5 taken together with these other studies, begin to paint a clearer picture of the role of ROS production by NAD(P)H oxidases in plaque biology and their relationship to clinical coronary syndromes. Future studies need to investigate more directly how molecular regulation of NAD(P)H oxidase components is related to the roles of macrophage and SMCs in mediating plaque stability. ROS production by both macrophages and SMCs and the subsequent effects of ROS on SMC phenotype, growth, and apoptosis may provide novel potential targets for modifying plaque stability in human atherosclerosis.FootnotesCorrespondence to Professor K.M. Channon, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail [email protected] References 1 Wolin MS. Interactions of oxidants with vascular signaling systems. Arterioscler Thromb Vasc Biol. 2000; 20: 1430–1442.CrossrefMedlineGoogle Scholar2 Guzik TJ, West NEJ, Black E, McDonald D, Ratnatunga C, Pillai R, Channon KM. Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res. 2000; 86: e85–e90.CrossrefMedlineGoogle Scholar3 Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatunga C, Pillai R, Channon KM. Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation. 2002; 105: 1656–1662.LinkGoogle Scholar4 Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000; 86: 494–501.CrossrefMedlineGoogle Scholar5 Azumi H, Inoue N, Ohashi Y, Terashima M, Mori T, Fujita H, Awano K, Kobayashi K, Maeda K, Hata K, Shinke T, Kobayashi S, Hirata K, Kawashima S, Itabe H, Hayashi Y, Imajoh-Ohmi S, Itoh H, Yokoyama M. Superoxide generation in directional coronary atherectomy specimens of patients with angina pectoris: important role of NAD(P)H oxidase. Arterioscler Thromb Vasc Biol. 2002; 22: 1838–1844.LinkGoogle Scholar6 Azumi H, Inoue N, Takeshita S, Rikitake Y, Kawashima S, Hayashi Y, Itoh H, Yokoyama M. Expression of NADH/NADPH oxidase p22phox in human coronary arteries. Circulation. 1999; 100: 1494–1498.CrossrefMedlineGoogle Scholar7 Kalinina N, Agrotis A, Tararak E, Antropova Y, Kanellakis P, Ilyinskaya O, Quinn MT, Smirnov V, Bobik A. Cytochrome b558—dependent NAD(P)H oxidase—phox units in smooth muscle and macrophages of atherosclerotic lesions. Arterioscler Thromb Vasc Biol. In press.Google Scholar8 Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro: implications for atherosclerotic plaque stability. J Clin Invest. 1996; 98: 2572–2579.CrossrefMedlineGoogle Scholar9 West NEJ, Guzik TJ, Black E, Channon KM. Enhanced superoxide production in experimental venous bypass graft intimal hyperplasia: role of NAD(P)H oxidase. Arterioscler Thromb Vasc Biol. 2001; 21: 189–194.CrossrefMedlineGoogle Scholar10 Lassegue B, Sorescu D, Szocs K, Yin Q, Akers M, Zhang Y, Grant SL, Lambeth JD, Griendling KK. Novel gp91(phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res. 2001; 88: 888–894.CrossrefMedlineGoogle Scholar11 Szocs K, Lassegue B, Sorescu D, Hilenski LL, Valppu L, Couse TL, Wilcox JN, Quinn MT, Lambeth JD, Griendling KK. Upregulation of Nox-based NAD(P)H oxidases in restenosis after carotid injury. Arterioscler Thromb Vasc Biol. 2002; 22: 21–27.CrossrefMedlineGoogle Scholar12 Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, Taylor WR, Griendling KK. Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation. 2002; 105: 1429–1435.LinkGoogle Scholar13 Vecchione C, Brandes RP. Withdrawal of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors elicits oxidative stress and induces endothelial dysfunction in mice. Circ Res. 2002; 91: 173–179.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Prasad K (2021) AGE–RAGE Stress and Coronary Artery Disease, International Journal of Angiology, 10.1055/s-0040-1721813, 30:01, (004-014), Online publication date: 1-Mar-2021. Gramlich Y, Daiber A, Buschmann K, Oelze M, Vahl C, Münzel T and Hink U (2018) Oxidative Stress in Cardiac Tissue of Patients Undergoing Coronary Artery Bypass Graft Surgery: The Effects of Overweight and Obesity, Oxidative Medicine and Cellular Longevity, 10.1155/2018/6598326, 2018, (1-13), Online publication date: 17-Dec-2018. Okafor O, Farrington K and Gorog D (2017) Allopurinol as a therapeutic option in cardiovascular disease, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2016.12.004, 172, (139-150), Online publication date: 1-Apr-2017. Xiao L, Liu L, Guo X, Zhang S, Wang J, Zhou F, Liu L, Tang Y and Yao P (2017) Quercetin attenuates high fat diet-induced atherosclerosis in apolipoprotein E knockout mice: A critical role of NADPH oxidase, Food and Chemical Toxicology, 10.1016/j.fct.2017.03.048, 105, (22-33), Online publication date: 1-Jul-2017. Wang X, Chen L and Zhang Q (2016) Increased Serum Level of Growth Differentiation Factor 15 (GDF-15) is Associated with Coronary Artery Disease, Cardiovascular Therapeutics, 10.1111/1755-5922.12184, 34:3, (138-143), Online publication date: 1-Jun-2016. Gohbara M, Hibi K, Mitsuhashi T, Maejima N, Iwahashi N, Kataoka S, Akiyama E, Tsukahara K, Kosuge M, Ebina T, Umemura S and Kimura K (2016) Glycemic Variability on Continuous Glucose Monitoring System Correlates With Non-Culprit Vessel Coronary Plaque Vulnerability in Patients With First-Episode Acute Coronary Syndrome – Optical Coherence Tomography Study –, Circulation Journal, 10.1253/circj.CJ-15-0790, 80:1, (202-210), . Fredman G, Hellmann J, Proto J, Kuriakose G, Colas R, Dorweiler B, Connolly E, Solomon R, Jones D, Heyer E, Spite M and Tabas I (2016) An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques, Nature Communications, 10.1038/ncomms12859, 7:1, Online publication date: 1-Nov-2016. Pereira P, Pernomian L, Côco H, Gomes M, Franco J, Marchi K, Hipólito U, Uyemura S, Tirapelli C and de Oliveira A (2016) Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia, European Journal of Pharmacology, 10.1016/j.ejphar.2016.04.008, 781, (1-9), Online publication date: 1-Jun-2016. Sun Y, He J, Tian J, Xie Z, Wang C and Yu B (2015) Association of circulating levels of neopterin with non-culprit plaque vulnerability in CAD patients an angiogram, optical coherent tomography and intravascular ultrasound study, Atherosclerosis, 10.1016/j.atherosclerosis.2015.04.818, 241:1, (138-142), Online publication date: 1-Jul-2015. Gustafsson H, Hallbeck M, Norell M, Lindgren M, Engström M, Rosén A and Zachrisson H (2013) Fe(III) distribution varies substantially within and between atherosclerotic plaques, Magnetic Resonance in Medicine, 10.1002/mrm.24687, 71:2, (885-892), Online publication date: 1-Feb-2014. Hermida N and Balligand J (2014) Low-Density Lipoprotein-Cholesterol-Induced Endothelial Dysfunction and Oxidative Stress: The Role of Statins, Antioxidants & Redox Signaling, 10.1089/ars.2013.5537, 20:8, (1216-1237), Online publication date: 10-Mar-2014. Streeter J, Thiel W, Brieger K and Miller Jr. F (2012) Opportunity Nox: The Future of NADPH Oxidases as Therapeutic Targets in Cardiovascular Disease, Cardiovascular Therapeutics, 10.1111/j.1755-5922.2011.00310.x, 31:3, (125-137), Online publication date: 1-Jun-2013. Botella-Carretero J, Balsa J, Vázquez C, Peromingo R, Díaz-Enriquez M and Escobar-Morreale H (2008) Retinol and α-Tocopherol in Morbid Obesity and Nonalcoholic Fatty Liver Disease, Obesity Surgery, 10.1007/s11695-008-9686-5, 20:1, (69-76), Online publication date: 1-Jan-2010. Churchman A, Anwar A, Li F, Sato H, Ishii T, Mann G and Siow R (2009) Transforming growth factor‐β 1 elicits Nrf2‐mediated antioxidant responses in aortic smooth muscle cells , Journal of Cellular and Molecular Medicine, 10.1111/j.1582-4934.2009.00874.x, 13:8b, (2282-2292), Online publication date: 2-Aug-2009. Rizk S and Sabri N (2009) Evaluation of clinical activity and safety of Daflon 500 mg in type 2 diabetic female patients, Saudi Pharmaceutical Journal, 10.1016/j.jsps.2009.08.008, 17:3, (199-207), Online publication date: 1-Jul-2009. CHANG D, WANG F, ZHAO Y and PAN H (2008) Evaluation of Oxidative Stress in Colorectal Cancer Patients, Biomedical and Environmental Sciences, 10.1016/S0895-3988(08)60043-4, 21:4, (286-289), Online publication date: 1-Aug-2008. Wang Y, Li H, Diao Y, Li H, Zhang Y, Yin C, Cui Y, Ma Q, Fang X, Zhou Y and Yang Y (2008) Relationship Between Oxidized LDL Antibodies and Different Stages of Esophageal Carcinoma, Archives of Medical Research, 10.1016/j.arcmed.2008.08.002, 39:8, (760-767), Online publication date: 1-Nov-2008. Iliodromitis E, Andreadou I, Markantonis-Kyroudis S, Mademli K, Kyrzopoulos S, Georgiadou P and Kremastinos D (2007) The effects of tirofiban on peripheral markers of oxidative stress and endothelial dysfunction in patients with acute coronary syndromes, Thrombosis Research, 10.1016/j.thromres.2006.02.002, 119:2, (167-174), Online publication date: 1-Jan-2007. Bedard K and Krause K (2007) The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology, Physiological Reviews, 10.1152/physrev.00044.2005, 87:1, (245-313), Online publication date: 1-Jan-2007. Maksimenko A (2007) Extracellular oxidative damage of vascular walls and their protection using antioxidant enzymes, Pharmaceutical Chemistry Journal, 10.1007/s11094-007-0053-y, 41:5, (235-243), Online publication date: 1-May-2007. Suzuki K, Inoue T, Hioki R, Ochiai J, Kusuhara Y, Ichino N, Osakabe K, Hamajima N and Ito Y (2006) Association of abdominal obesity with decreased serum levels of carotenoids in a healthy Japanese population, Clinical Nutrition, 10.1016/j.clnu.2006.01.025, 25:5, (780-789), Online publication date: 1-Oct-2006. Madamanchi N, Vendrov A and Runge M (2004) Oxidative Stress and Vascular Disease, Arteriosclerosis, Thrombosis, and Vascular Biology, 25:1, (29-38), Online publication date: 1-Jan-2005. MADAMANCHI N, HAKIM Z and RUNGE M (2005) Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes, Journal of Thrombosis and Haemostasis, 10.1111/j.1538-7836.2004.01085.x, 3:2, (254-267), Online publication date: 1-Feb-2005. Lapenna D, Ciofani G, Pierdomenico S, Giamberardino M and Cuccurullo F (2004) Copper, zinc superoxide dismutase plus hydrogen peroxide: a catalytic system for human lipoprotein oxidation, FEBS Letters, 10.1016/j.febslet.2004.11.081, 579:1, (245-250), Online publication date: 3-Jan-2005. Abudu N, Miller J, Attaelmannan M and Levinson S (2004) Vitamins in human arteriosclerosis with emphasis on vitamin C and vitamin E, Clinica Chimica Acta, 10.1016/j.cccn.2003.09.018, 339:1-2, (11-25), Online publication date: 1-Jan-2004. Yao Q, Pecoits-Filho R, Lindholm B and Stenvinkel P (2009) Traditional and non-traditional risk factors as contributors to atherosclerotic cardiovascular disease in end-stage renal disease, Scandinavian Journal of Urology and Nephrology, 10.1080/00365590410031715, 38:5, (405-416), Online publication date: 1-Jan-2004. Suzuki K, Ito Y, Wakai K, Kawado M, Hashimoto S, Toyoshima H, Kojima M, Tokudome S, Hayakawa N, Watanabe Y, Tamakoshi K, Suzuki S, Ozasa K and Tamakoshi A (2004) Serum Oxidized Low-Density Lipoprotein Levels and Risk of Colorectal Cancer: A Case-Control Study Nested in the Japan Collaborative Cohort Study, Cancer Epidemiology, Biomarkers & Prevention, 10.1158/1055-9965.1781.13.11, 13:11, (1781-1787), Online publication date: 1-Nov-2004. Stuart-Shor E, Buselli E, Carroll D and Forman D (2003) Are Psychosocial Factors Associated With the Pathogenesis and Consequences of Cardiovascular Disease in the Elderly?, The Journal of Cardiovascular Nursing, 10.1097/00005082-200307000-00003, 18:3, (169-183), Online publication date: 1-Jul-2003. Stenvinkel P, Pecoits-Filho R and Lindholm B (2003) Coronary Artery Disease in End-Stage Renal Disease: No Longer a Simple Plumbing Problem, Journal of the American Society of Nephrology, 10.1097/01.ASN.0000069165.79509.42, 14:7, (1927-1939), Online publication date: 1-Jul-2003. Phelan S, Wang X, Wallbrandt P, Forsman-Semb K and Paigen B (2003) Overexpression of Prdx6 reduces H2O2 but does not prevent diet-induced atherosclerosis in the aortic root, Free Radical Biology and Medicine, 10.1016/S0891-5849(03)00462-3, 35:9, (1110-1120), Online publication date: 1-Nov-2003. Gole H, Tharp D, Bowles D and Jourd’heuil D (2014) Upregulation of Intermediate-Conductance Ca2+-Activated K+ Channels (KCNN4) in Porcine Coronary Smooth Muscle Requires NADPH Oxidase 5 (NOX5), PLoS ONE, 10.1371/journal.pone.0105337, 9:8, (e105337) Song L, Zhang J, Lai R, Li Q, Ju J and Xu H (2021) Chinese Herbal Medicines and Active Metabolites: Potential Antioxidant Treatments for Atherosclerosis, Frontiers in Pharmacology, 10.3389/fphar.2021.675999, 12 November 2002Vol 22, Issue 11 Advertisement Article InformationMetrics https://doi.org/10.1161/01.ATV.0000042203.08210.17PMID: 12426198 Originally publishedNovember 1, 2002 PDF download Advertisement