Elevated plasma levels of MMP-12 are associated with atherosclerotic burden and symptomatic cardiovascular disease in subjects with type 2 diabetes

Isabel Goncalves, Eva Bengtsson, Helen M. Colhoun, Angela C. Shore, Carlo Palombo, Andrea Natali, Andreas Edsfeldt, Pontus Dunér, Gunilla Nordin Fredrikson, Harry Björkbacka, Gerd Östling, Kunihiko Aizawa, Francesco Casanova, Margaretha Persson, Kim Gooding, David Strain, Faisel Khan, Helen C. Looker, Fiona Adams, Jill Belch & 6 others Silvia Pinnoli, Elena Venturi, Michaela Kozakova, Li-Ming Gan, Volker Schnecke, Jan Nilsson

    Research output: Contribution to journalArticle

    38 Citations (Scopus)

    Abstract

    Objective-Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus.

    Approach and Results-Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro-and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up.

    Conclusions-The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.

    Original languageEnglish
    Pages (from-to)1723-1731
    Number of pages9
    JournalArteriosclerosis, Thrombosis, and Vascular Biology
    Volume35
    Issue number7
    Early online date7 May 2015
    DOIs
    Publication statusPublished - 27 Jul 2015

    Fingerprint

    Matrix Metalloproteinase 12
    Matrix Metalloproteinase 7
    Type 2 Diabetes Mellitus
    Atherosclerosis
    Cardiovascular Diseases
    Matrix Metalloproteinases
    Biomarkers
    Diet
    Ankle Brachial Index
    Matrix Metalloproteinase 3
    Carotid Intima-Media Thickness
    Matrix Metalloproteinase 1
    Vascular Stiffness
    Carotid Endarterectomy
    Extracellular Matrix Proteins
    Incidence
    Neoplasms
    Inflammation
    Technology
    Kidney

    Keywords

    • atherosclerosis
    • cardiovascular disease
    • diabetes
    • matrix metalloproteinase

    Cite this

    Goncalves, Isabel ; Bengtsson, Eva ; Colhoun, Helen M. ; Shore, Angela C. ; Palombo, Carlo ; Natali, Andrea ; Edsfeldt, Andreas ; Dunér, Pontus ; Fredrikson, Gunilla Nordin ; Björkbacka, Harry ; Östling, Gerd ; Aizawa, Kunihiko ; Casanova, Francesco ; Persson, Margaretha ; Gooding, Kim ; Strain, David ; Khan, Faisel ; Looker, Helen C. ; Adams, Fiona ; Belch, Jill ; Pinnoli, Silvia ; Venturi, Elena ; Kozakova, Michaela ; Gan, Li-Ming ; Schnecke, Volker ; Nilsson, Jan. / Elevated plasma levels of MMP-12 are associated with atherosclerotic burden and symptomatic cardiovascular disease in subjects with type 2 diabetes. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2015 ; Vol. 35, No. 7. pp. 1723-1731.
    @article{7e14fb78ba584bf891b33a2f600149ac,
    title = "Elevated plasma levels of MMP-12 are associated with atherosclerotic burden and symptomatic cardiovascular disease in subjects with type 2 diabetes",
    abstract = "Objective-Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. Approach and Results-Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro-and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malm{\"o} Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malm{\"o} Diet and Cancer subjects who had a coronary event during follow-up. Conclusions-The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.",
    keywords = "atherosclerosis, cardiovascular disease, diabetes, matrix metalloproteinase",
    author = "Isabel Goncalves and Eva Bengtsson and Colhoun, {Helen M.} and Shore, {Angela C.} and Carlo Palombo and Andrea Natali and Andreas Edsfeldt and Pontus Dun{\'e}r and Fredrikson, {Gunilla Nordin} and Harry Bj{\"o}rkbacka and Gerd {\"O}stling and Kunihiko Aizawa and Francesco Casanova and Margaretha Persson and Kim Gooding and David Strain and Faisel Khan and Looker, {Helen C.} and Fiona Adams and Jill Belch and Silvia Pinnoli and Elena Venturi and Michaela Kozakova and Li-Ming Gan and Volker Schnecke and Jan Nilsson",
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    journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
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    }

    Goncalves, I, Bengtsson, E, Colhoun, HM, Shore, AC, Palombo, C, Natali, A, Edsfeldt, A, Dunér, P, Fredrikson, GN, Björkbacka, H, Östling, G, Aizawa, K, Casanova, F, Persson, M, Gooding, K, Strain, D, Khan, F, Looker, HC, Adams, F, Belch, J, Pinnoli, S, Venturi, E, Kozakova, M, Gan, L-M, Schnecke, V & Nilsson, J 2015, 'Elevated plasma levels of MMP-12 are associated with atherosclerotic burden and symptomatic cardiovascular disease in subjects with type 2 diabetes', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 35, no. 7, pp. 1723-1731. https://doi.org/10.1161/ATVBAHA.115.305631

    Elevated plasma levels of MMP-12 are associated with atherosclerotic burden and symptomatic cardiovascular disease in subjects with type 2 diabetes. / Goncalves, Isabel; Bengtsson, Eva; Colhoun, Helen M.; Shore, Angela C.; Palombo, Carlo; Natali, Andrea; Edsfeldt, Andreas; Dunér, Pontus; Fredrikson, Gunilla Nordin; Björkbacka, Harry; Östling, Gerd; Aizawa, Kunihiko; Casanova, Francesco; Persson, Margaretha; Gooding, Kim; Strain, David; Khan, Faisel; Looker, Helen C.; Adams, Fiona; Belch, Jill; Pinnoli, Silvia; Venturi, Elena; Kozakova, Michaela; Gan, Li-Ming; Schnecke, Volker; Nilsson, Jan (Lead / Corresponding author).

    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 35, No. 7, 27.07.2015, p. 1723-1731.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Elevated plasma levels of MMP-12 are associated with atherosclerotic burden and symptomatic cardiovascular disease in subjects with type 2 diabetes

    AU - Goncalves, Isabel

    AU - Bengtsson, Eva

    AU - Colhoun, Helen M.

    AU - Shore, Angela C.

    AU - Palombo, Carlo

    AU - Natali, Andrea

    AU - Edsfeldt, Andreas

    AU - Dunér, Pontus

    AU - Fredrikson, Gunilla Nordin

    AU - Björkbacka, Harry

    AU - Östling, Gerd

    AU - Aizawa, Kunihiko

    AU - Casanova, Francesco

    AU - Persson, Margaretha

    AU - Gooding, Kim

    AU - Strain, David

    AU - Khan, Faisel

    AU - Looker, Helen C.

    AU - Adams, Fiona

    AU - Belch, Jill

    AU - Pinnoli, Silvia

    AU - Venturi, Elena

    AU - Kozakova, Michaela

    AU - Gan, Li-Ming

    AU - Schnecke, Volker

    AU - Nilsson, Jan

    PY - 2015/7/27

    Y1 - 2015/7/27

    N2 - Objective-Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. Approach and Results-Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro-and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. Conclusions-The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.

    AB - Objective-Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. Approach and Results-Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro-and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. Conclusions-The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.

    KW - atherosclerosis

    KW - cardiovascular disease

    KW - diabetes

    KW - matrix metalloproteinase

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    U2 - 10.1161/ATVBAHA.115.305631

    DO - 10.1161/ATVBAHA.115.305631

    M3 - Article

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    SP - 1723

    EP - 1731

    JO - Arteriosclerosis, Thrombosis, and Vascular Biology

    JF - Arteriosclerosis, Thrombosis, and Vascular Biology

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