Advertisement

Intraplaque MMP-8 levels are increased in asymptomatic patients with carotid plaque progression on ultrasound

      Abstract

      Carotid atherosclerotic plaque remodelling and increased risk of symptomatic plaque rupture seem to be partially mediated by matrix metalloproteinases (MMPs). In this study, we have investigated whether different MMPs are related to carotid atherosclerosis or to recent ischaemic brain disease.
      Eighty-four consecutive patients undergoing carotid endarterectomy for symptomatic and asymptomatic disease were studied. Plaques were analysed by ultrasound and later by morphology. Plasma MMP-2, MMP-8 and MMP-9 levels were quantified by ELISA. MMP expression and activity in carotid plaques was analysed by Western blotting and in situ zymography. Results were analysed with respect to plaque stability, morphology, symptomatic disease, presence of vascular risk factors and plasma markers of acute inflammation as high sensitivity C-reactive protein (hsCRP), fibrinogen, D-dimer and white blood cell counts.
      Patients with hypoechogenic plaques on ultrasound had more plasma MMP-8 (p = 0.04) and increased MMP activity as assessed by in situ zymography. Asymptomatic patients with plaque progression had more active intraplaque MMP-8 than asymptomatic patients without plaque progression. Presence of recent intraplaque haemorrhage or past history of CAD was related to increased activity of MMPs as assessed by in situ zymography (p < 0.01, CI 95% 0.8–1.0). Plasma MMP-8 and MMP-9, but not MMP-2 levels, decrease with time after ischaemic stroke. Patients with hypertension had more intraplaque active MMP-9 than normotensive (p = 0.03, CI 95% 0.7–1.0).
      Hypoechogenic carotid plaques had increased MMP activity and asymptomatic patients with plaque progression show increase intraplaque MMP-8 levels.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Beaudeux J.
        • Burc L.
        • Imbert-Bismut F.
        • et al.
        Serum plasma pregnancy-associated protein A: a potential marker of echogenic carotid atherosclerotic plaques in asymptomatic hyperlipidemic subjects at high cardiovascular risk.
        Arterioscler Thromb Vasc Biol. 2003; 23: e7-e10
        • Loftus I.
        • Naylor A.
        • Bell P.
        • Thompson M.
        Matrix metalloproteinases and atherosclerotic plaque instability.
        Br J Surg. 2002; 89: 680-694
        • Herman M.
        • Sukhova G.
        • Libby P.
        • et al.
        Expression of neutrophil collagenase (matrix metalloprotease-8) in human atheroma.
        Circulation. 2001; 104: 1899-1904
        • Sukhova G.
        • Schonbeck U.
        • Rabkin E.
        • et al.
        Evidence fro increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques.
        Circulation. 1999; 99: 2503-2509
        • Bini A.
        • Mann K.
        • Kudryk B.
        • Schoen F.
        Noncollagenous bone matrix proteins, calcification, and thrombosis in carotid artery atherosclerosis.
        Arterioscler Thromb Vasc Biol. 1999; 18: 1852-1861
        • Somerville R.
        • Oblander S.
        • Apte S.
        Matrix metalloproteinases: old dogs with new tricks.
        Genome Biol. 2003; 4: 216
        • Montaner J.
        • Alvarez-Sabín J.
        • Molina C.
        • et al.
        Matrix metalloproteinase expression after human cardioembolic stroke. Temporal profile and relation to neurological impairment.
        Stroke. 2001; 32: 1759-1766
        • Montaner J.
        • Alvarez-Sabín J.
        • Molina C.
        • et al.
        Matrix metalloproteinase (MMP-9) expression is related to hemorrhagic transformation after cardioembolic stroke.
        Stroke. 2001; 32: 2762-2767
        • Montaner J.
        • Molina C.A.
        • Monasterio J.
        • et al.
        Matrix metalloproteinase (MMP-9) pre-treatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke.
        Circulation. 2003; 107: 598-603
        • Cipollone F.
        • Fazia M.
        • Iezzi A.
        • et al.
        Circulation. 2003; 107: 1479-1485
        • Beaudeux J.
        • Giral P.
        • Bruckert E.
        • et al.
        Serum matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 as potential markers of carotid atherosclerosis in infraclinical hyperlipidemia.
        Atherosclerosis. 2003; 169: 139-146
        • Uemura S.
        • Matsushita H.
        • Li W.
        • et al.
        Diabetes mellitus enhances vascular matrix metalloproteinases activity: role of oxidative stress.
        Circ Res. 2001; 88: 1291-1298
        • Ryan M.
        • Ramamurthy N.
        • Sorsa T.
        • Golub L.
        MMP-mediated events in diabetes.
        Ann NY Acad Sci. 1999; 878: 311-334
        • Gallis Z.
        • Sukhova G.
        • Lark M.
        • et al.
        Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.
        J Clin Invest. 1994; 94: 2493-2503
        • Knauper V.
        • Lopez-Otin C.
        • Smith B.
        Biochemical characterization of human collagenase-3.
        J Biol Chem. 1996; 271: 1544-1550
        • Herman M.
        • Sukhova G.
        • Libby P.
        • et al.
        Expression of neutrophil collagenase (MMP-8) in human atheroma.
        Circulation. 2001; 104: 1899-1906
        • Dollery C.
        • Owen C.
        • Sukhova G.
        • et al.
        Neutrophil elastase in human atherosclerotic plaques: production by macrophages.
        Circulation. 2003; 107: 2829-2836
        • Bladin C.
        • Alexandrov A.
        • Murphy J.
        • Maggisano R.
        • Norris J.
        Carotid stenosis index. A new method of measuring internal carotid artery stenosis.
        Stroke. 1995; 26: 230-234
        • Gray Weale A.
        • Graham J.
        • Burnett J.
        • Byrne K.
        • Lusby R.
        Carotid artery atheroma: a comparison of preoperative B-mode ultrasound appearance with carotid endarterectomy specimen pathology.
        Cardiovasc Surg. 1988; 29: 676-681
        • Stara H.
        • Chandler A.
        • Dinsmore R.
        • et al.
        A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.
        Circulation. 1995; 15: 1512-1531
        • Krupinski J.
        • Slevin M.
        • Marti E.
        • et al.
        Time-course phosphorylation of the mitogen activated protein (MAP) kinase group of signalling proteins and related molecules following middle cerebral artery occlusion (MCAO) in rats.
        Neuropathol Appl Neurobiol. 2003; 29: 144-158
        • Loy M.
        • Burggraf D.
        • Martens K.
        • et al.
        A gelatin in situ overlay technique localizes brain matrix metalloproteinase activity in experimental focal cerebral ischemia.
        J Neurosci Methods. 2002; 15: 125-133
        • Zalewska T.
        • Ziemka-Nalecz M.
        • Sarnowska A.
        • Domanska-Janik K.
        Involvement of MMPs in delayed neuronal death after global ischemia.
        Acta Neurobiol Exp. 2002; 62: 53-61
        • Daugherty A.
        • Dunn J.
        • Rateri D.
        Myeloproxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions.
        J Clin Invest. 1994; 94: 437-444
        • Ivan E.
        • Khatri J.
        • Johnson C.
        • et al.
        Expansive arterial remodelling is associated with increased neointimal macrophage foam cell content: the murine model of macrophage-rich carotid artery lesions.
        Circulation. 2002; 105: 2686-2691
        • Malik N.
        • Greenfield B.
        • Wahl A.
        Activation of human monocytes through CD40 induces matrix metalloproteinases.
        J Immunol. 1996; 156: 3952-3960
        • Rekhter M.
        • Zhang K.
        • Narayanan A.
        Type I collagen gene expression in human atherosclerosis: localization to specific plaque regions.
        Am J Pathol. 1993; 143: 1634-1648
        • Horstmann S.
        • Kalb P.
        • Koziol J.
        • Gardner H.
        • Wagner S.
        Profiles of matrix metalloproteases, their inhibitors, and lamin in stroke patients.
        Stroke. 2003; 34: 2165
        • Loftus I.
        • Naylor A.
        • Goodall S.
        • et al.
        Increased matrix metalloproteinase-9 activity in unstable carotid plaques.
        Stroke. 2000; 31: 40-47
        • Loftus I.
        • Naylor A.
        • Goodall S.
        • et al.
        Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption.
        Stroke. 2000; 31: 40-47
        • van der Waal A.
        • Piek J.
        • de Boer O.
        • et al.
        Recent activation of the plaque immune response in coronary lesions underlying acute coronary syndromes.
        Heart. 1998; 80: 14-18
        • Feinberg W.
        • Erickson L.
        • Bruck D.
        • Kittelson J.
        Hemostatic markers in acute ischemic stroke: association with stroke type, severity, and outcome.
        Stroke. 1996; 27: 1296-1300
        • Di Napoli M.
        • Papa F.
        • Bocola V.
        Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke.
        Stroke. 2001; 32: 133-138
        • Ridker P.
        Clinical application of C-reactive protein for cardiovascular disease detection and prevention.
        Circulation. 2003; 107: 363-371
        • Grau A.
        Infection, inflammation, and cerebrovascular ischemia.
        Neurology. 1997; 49: S47-S51
        • Rost N.
        • Wolf P.
        • Kase C.
        • et al.
        Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study.
        Stroke. 2001; 32: 2575-2579
        • Meer I.
        • Maat M.
        • Hak A.
        • et al.
        C-reactive protein predicts progression of atherosclerosis measured at various sites in the arterial tree.
        Stroke. 2002; 33: 2750-2758
        • Magyar M.
        • Szikszai Z.
        • Balla J.
        • et al.
        Early-onset carotid atherosclerosis is associated with increased intima-media thickness and elevated serum levels of inflammatory markers.
        Stroke. 2003; 34: 58-65
        • Del Rincon I.
        • Williams K.
        • Stern M.
        • et al.
        Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects.
        Arthritis Rheum. 2003; 48: 1833-1840
        • Axisa B.
        • Loftus I.
        • Naylor A.
        • et al.
        Prospective, randomized, double-blind trial investigating the effect of doxycycline on matrix metalloproteinase expression within atherosclerotic carotid plaques.
        Stroke. 2002; 33: 2858-2863