Cosentino, Francesco

Paneni, Francesco

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EDITORIALAdvanced glycation endproducts and plaqueinstability: a link beyond diabetesFrancesco Paneni1,2* and Francesco Cosentino1,21Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zu¨rich, Switzerland; and 2Cardiology, Department of Clinical and Molecular Medicine,University of Rome ‘Sapienza’, ItalyOnline publish-ahead-of-print 31 October 2013This editorial refers to ‘Higher levels of advanced glycationendproducts in human carotid atherosclerotic plaques areassociated with a rupture-prone phenotype’†, by N.M.J.Hanssen et al., on page 1137Despite clear advances in the treatment of vascular disease, we arestill far from the understanding and valid assessment of the naturalhistory of atherosclerotic plaque. Several studies have shown thatthe vulnerable plaque is the main culprit for ischaemic cardiac andcerebral events, but reliable indicators of plaque instability remainelusive in clinical practice.1 This aspect deserves attention sincerupture of carotid plaques explains at least 15–20% of all ischaemicstrokes or transient ischaemic attacks.2 Over 15 million people peryear suffer strokes worldwide, resulting in 5 million deaths, and an add-itional 5 million remain permanently disabled.2 Treatment of carotidartery stenosis by endoarterectomy or stenting can significantlyreduce stroke risk, but it is also accompanied by surgery-related mor-bidityandmortality.1,2Moreover,notall carotidarteryplaquesbecomesymptomatic and result in ischaemic events. In this perspective, theidentification of carotid plaques at high risk for neurological events isfundamental to the selection of patients for vascular interventions.Different processes involved in the progression of atheroscleroticlesions have been associated with plaque vulnerability.3 Previousseminal investigations have clearly shown that inflammation, prote-olysis, and apoptosis are major drivers of plaque complexity and fra-gility.3 Pathological featuresof unstableplaques are representedbyanatheromatous thin fibrous cap, large necrotic core, infiltration of in-flammatory cells, and scarce calcification. Despite available imagingtechniques providing an exhaustive macroscopic characterizationof the plaque, the innermechanisms involved remain tobe largelyelu-cidated and characterization of the molecular processes is achievedonly at post-operative or post-mortem examination.1 The assess-ment of early markers of plaque vulnerability is an attractive challengeto select candidates for mechanism-based therapeutic strategies.Among different biomarkers, advanced glycation endproducts(AGEs) have been linked to the atherosclerotic process and areemerging as a novel signature of atherosclerotic disease.4 AGEs area large family of extensively sugar-modified proteins which can beformed in plaques as a consequences of increased metabolic activ-ity.1,4 It is well established that AGEs are present in atheroscleroticlesions.5 Of note, inhibition of synthesis of AGEs prevents or attenu-atesatherosclerosis inexperimentalmodels.4,5Despite the linkbetweenAGEs and atherosclerosis, their precise role in the context of athero-sclerotic plaque remains unclear.Hanssen and colleagues have now shown that AGE accumulationmay represent an indicator of plaque vulnerability.6 The authorsfound that two major AGEs, the methylglyoxal-derived 5-hydro-5-methylimidazolone (MG-H1) and N1 (carboxylmethyl)lysine(CML), measured with tandem mass spectrometry, were significantlyhigher in symptomatic as compared with asymptomatic carotidplaques. MG-H1 and CML were associated with increased levels ofthe inflammatory cytokines interleukin-8 (IL-8) and monocytechemoattractant protein 1 (MCP-1), as well as with higher activityof matrix metalloproteinase 9 (MMP-9), an important modulator ofplaque collagen content. Immunohistochemistry showed that AGEaccumulation occurs in macrophages, is mostly confined tohypoxic regions of the necrotic core, and co-localizes with the apop-totic marker caspase-3 (Figure 1). Interestingly, gene expression ofglyoxalase-1 (GLO1), the most important methylglyoxal-detoxifyingenzyme, was decreased in vulnerable as compared with stableplaques. A provocative finding of the present work is that MG-H1and CML were independently associated with a vulnerable plaquephenotype, regardless of diabetes. History of diabetes did notaffect the link between AGEs and plaque inflammation, and no corre-lations were found between fasting glycaemia and AGE levels, evenafter adjustment for glucose-lowering drugs. These findings suggestthe possibility that AGEs can also be considered markers of plaqueinflammation and instability in non-diabetic individuals. Indeed, themajor determinant of intraplaque protein glycation is the high meta-bolic activity of macrophages, leading to enhanced D-glucose uptakeand subsequent formation of AGEs (Figure 1). This assumption is sup-ported by the demonstration that positron emission tomography* Corresponding author. Cardiology & Cardiovascular Research, University of Zu¨rich, Switzerland. Tel: +41 44 635 5081, Fax: +41 44 635 68 27, Email: francesco.paneni@gmail.comThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.† doi:10.1093/eurheartj/eht402.Published on behalf of the European Society of Cardiology. All rights reserved.& The Author 2013. For permissions please email: journals.permissions@oup.comEuropean Heart Journal (2014) 35, 1095–1097doi:10.1093/eurheartj/eht454(PET)-based uptake of the glucose analogue [18F]fluorodeoxyglu-cose (18FDG) is enhanced in symptomatic carotid arteries of non-diabetic patients.7 Unfortunately, glycated haemoglobin (Hb1Ac)was not available in the study by Hanssen et al.6 and it is not possibleto rule out that chronic hyperglycaemia might also affect intraplaqueglucose content, leading to a further extent of protein glycation.Another interesting finding of this study is that hypoxia within thenecrotic core may trigger AGE formation in macrophages (Figure 1).Indeed, MG-H1 and CML co-localized with macrophage-rich andhypoxic regions, as assessed by pimonidazole staining. To investigatethe link between intraplaque hypoxia and AGE synthesis further,MG-H1 and CML levels were measured in human monocytes afterexposure to low oxygen concentrations (0.2%). Interestingly, invitro hypoxia enhanced AGE formation mostly via increased methyl-glyoxal (MGO) levels and GLO1 down-regulation (Figure 1). Thesefindings are in line with recent work showing that GLO1-dependentdetoxification is an important defender of vascular homeostasis.8However, a previous study from the same group showed that poly-morphisms in the GLO1 gene are not associated with vascular com-plications in two Dutch cohorts of patients with normal glucosemetabolism, impaired glucose tolerance, and type 2 diabetes melli-tus.9 Therefore, the exact contribution of GLO1 to humanFigure 1 Role of advanced glycation endproducts (AGEs) in plaque vulnerability. The AGEs MG-H1 and CML are synthesized in macrophages ofvulnerable carotid plaques due to high glucose uptake. MG-H1 and CML accumulation mostly occurs in the hypoxic region of the necrotic core.Inflammatory cytokines IL-8 and MCP-1 as well as MMP-9 trigger AGE formation and subsequent cell apoptosis via activation of caspase-3. Onthe other hand, down-regulation of the methylglyoxal-detoxifying enzyme GLO1 contributes to AGE accumulation. CML, Ne (carboxylmethyl)ly-sine; GLO1, glyoxalase-1; IL-8, interleukin-8; MCP-1, monocyte chemoattractant protein-1; MG-H1, 5-hydro-5-methylimidazolone; MMP-9,metalloproteinase-9; VSMCs, vascular smooth muscle cells.Editorial1096atherosclerosis remains to be elucidated. In this regard, Hanssen et al.propose that AGE accumulation may be the effect and not the causeof plaque inflammation.6 Indeed, the inflammatory in vitro effect oftumour necrosis factor-a (TNF-a) on IL-8, MCP-1, or MMP-9 isnot dependent on AGEs because the AGE inhibitor aminoguanidinereduced MGOandAGE formation but didnot affect IL-8,MCP-1, andMMP-9 expression. Moreover, incubation of monocytes with CMLor MGO did not increase the secretion of IL-8, MCP-1, andMMP-9.6 These findings are in contrast to previous work showingthat AGE–RAGE (AGE receptor) signalling leads to an increased oxi-dative burst via NADPH oxidase and mitogen-activated proteinkinases (ERK 1/2) with subsequent activation of nuclear factor-kB(NF-kB) and transcription of inflammatory genes.10 Thus, the AGEcontent in the plaque may be the result of a vicious cycle involving in-flammation, oxidative stress, AGEs, and NF-kB activation. In contrast,ifAGEs are just a consequence of plaque inflammation theycannot beconsidered early biomarkers of the atherosclerotic process butrather a mirror of the inflammatory milieu. A further interpretationis that the highly antigenic nature of CML primarily triggers an inflam-matory response in the subendothelial layer, favouring the athero-sclerotic process. This latter hypothesis may not be that unrealisticsince autoimmune responses have been postulated as potentialdrivers of vascular inflammation.11 In line with this interpretation,the RAGEs were not up-regulated in vulnerable plaques, suggestingthat AGE–RAGE interaction may be less relevant than intracellularaccumulation of AGEs. However, such a provocative finding ofnormal RAGE expression in unstable plaques deserves further inves-tigation. A phase II clinical trial demonstrated that pharmacologicalAGE degradation by the cross-link breaker ALT-711 reduced arterialpulse pressure and improved the compliance of large arteries, twoimportant pre-atherosclerotic features.12 Another study with benfo-tiamine prevented both macro- and microvascular endothelial dys-function and oxidative stress induced by an AGE-rich meal.13Moreover, the combined use of benfotiamine and a-lipoic acid nor-malized the elevated AGEs levels and blocked the enhancement ofhexosamine-modified protein formation in monocytes of patientswith type 1 diabetes.14 Based on these studies, AGE formation mayrepresent an upstream event triggering vascular inflammation, oxida-tive stress, and eventually plaque instability.In summary, Hanssen and colleagues demonstrate for the first timean intriguing link between AGEs and plaque phenotype. These resultsimply that AGEs may represent a putative biomarker of rupture-prone plaques, regardless of diabetes. However, several considera-tions should be taken into account before considering this cardiovas-cular risk stratification approach. While AGE levels in the plaquestrongly correlate with a vulnerable phenotype, it remains unclearwhether plasma or skin-derived AGEs similarly reflect this associ-ation. This aspect has important clinical implications since the assess-ment of AGEs in the carotid arteries can be performed only afterpost-operative examination and it is not applicable as a screeningtool. In this context, previous work suggested that measuring AGEsin skin using autofluorescence may provide important informationon risk stratification in diabetic patients. This study involving 972 dia-betic patients showed that the addition of skin AGEs to the UKPDSrisk engine resulted in re-classification of 27% of the patients fromthe low- to the high-risk group.15 The 10-year cardiovascular eventrate was higher in patients with a UKPDS score .10% when skinAGEs were above the median (56% vs. 39%).Undoubtedly, this work has shed some light on the intriguing issueof AGE levels as early biomarker of plaque instability. However, add-itional pre-clinical studies are mandatory to understand whetherAGE inhibition may prevent or delay atherosclerotic complications.Conflict of interest: none declared.References1. Hermus L, Lefrandt JD, Tio RA, Breek JC, Zeebregts CJ. Carotid plaque formationand serum biomarkers. Atherosclerosis 2010;213:21–29.2. MughalMM, Khan MK, DeMarco JK, Majid A, Shamoun F, Abela GS. Symptomatic andasymptomatic carotid artery plaque. Expert Rev Cardiovasc Ther 2011;9:1315–1330.3. Nighoghossian N, Derex L, Douek P. The vulnerable carotid artery plaque: currentimaging methods and new perspectives. Stroke 2005;36:2764–2772.4. Jandeleit-Dahm K, Cooper ME. The role of AGEs in cardiovascular disease. CurrPharm Des 2008;14:979–986.5. Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascularinflammation: implications for accelerated atherosclerosis in diabetes.Cardiovasc Res2004;63:582–592.6. Hanssen NMJ, Wouters K, Huijberts MS, Gijbels MJ, Sluimer JC, Scheijen JLJM,Heeneman S, Biessen EAL, Daemen MJAP, Brownlee M, de Kleiijn DP,Stehouwer CDA, Pasterkamp G, Schalkwijk CG. Higher levels of advanced gly-cation endproducts in human carotid atherosclerotic plaques are associated witha rupture-prone phenotype. Eur Heart J 2014;35:1137–1146.7. Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, Johnstrom P,Davenport AP, Kirkpatrick PJ, Arch BN, Pickard JD, Weissberg PL. Imaging athero-sclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emissiontomography. Circulation 2002;105:2708–2711.8. Berner AK, Brouwers O, Pringle R, Klaassen I, Colhoun L, McVicar C, Brockbank S,Curry JW, Miyata T, Brownlee M, Schlingemann RO, Schalkwijk C, Stitt AW. Protec-tion against methylglyoxal-derived ages by regulation of glyoxalase 1 prevents retinalneuroglial and vasodegenerative pathology. Diabetologia 2012;55:845–854.9. Engelen L, Ferreira I, Brouwers O, Henry RM, Dekker JM, Nijpels G, Heine RJ, vanGreevenbroek MM, van der Kallen CJ, Blaak EE, Feskens EJ, ten Cate H,Stehouwer CD, Schalkwijk CG. Polymorphisms in glyoxalase 1 gene are not asso-ciated with vascular complications: the Hoorn and CoDAM studies. J Hypertens2009;27:1399–1403.10. Yan SF, Ramasamy R, Schmidt AM. The RAGE axis: a fundamental mechanism signal-ing danger to the vulnerable vasculature. Circ Res 2010;106:842–853.11. Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and op-portunities. Science 2013;339:166–172.12. Kass DA, ShapiroEP, KawaguchiM, Capriotti AR, ScuteriA, deGroofRC, LakattaEG.Improved arterial compliance by a novel advanced glycation end-product crosslinkbreaker. Circulation 2001;104:1464–1470.13. Stirban A, Negrean M, Stratmann B, Gawlowski T, Horstmann T, Gotting C,Kleesiek K, Mueller-Roesel M, Koschinsky T, Uribarri J, Vlassara H, Tschoepe D. Ben-fotiamine prevents macro- and microvascular endothelial dysfunction and oxidativestress following a meal rich in advanced glycation end products in individuals withtype 2 diabetes. Diabetes Care 2006;29:2064–2071.14. Du X, Edelstein D, Brownlee M. Oral benfotiamine plus alpha-lipoic acid normalisescomplication-causing pathways in type 1 diabetes.Diabetologia2008;51:1930–1932.15. Meerwaldt R, Graaff R, Oomen PH, Links TP, Jager JJ, Alderson NL, Thorpe SR,Baynes JW, Gans RO, Smit AJ. Simple non-invasive assessment of advanced glycationendproduct accumulation. Diabetologia 2004;47:1324–1330Editorial 1097

Advanced glycation endproducts and plaque instability: a link beyond diabetes

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