title: Matrix metalloproteinase 8 degrades apolipoprotein A-I and reduces its cholesterol efflux capacity.
abstract: Various cell types in atherosclerotic lesions express matrix metalloproteinase (MMP)-8. We investigated whether MMP-8 affects the structure and antiatherogenic function of apolipoprotein (apo) A-I, the main protein component of HDL particles. Furthermore, we studied serum lipid profiles and cholesterol efflux capacity in MMP-8-deficient mouse model. Incubation of apoA-I (28 kDa) with activated MMP-8 yielded 22 kDa and 25 kDa apoA-I fragments. Mass spectrometric analyses revealed that apoA-I was cleaved at its carboxyl-terminal part. Treatment of apoA-I and HDL with MMP-8 resulted in significant reduction (up to 84%, P < 0.001) in their ability to facilitate cholesterol efflux from cholesterol-loaded THP-1 macrophages. The cleavage of apoA-I by MMP-8 and the reduction in its cholesterol efflux capacity was inhibited by doxycycline. MMP-8-deficient mice had significantly lower serum triglyceride (TG) levels (P = 0.003) and larger HDL particles compared with wild-type (WT) mice. However, no differences were observed in the apoA-I levels or serum cholesterol efflux capacities between the mouse groups. Proteolytic modification of apoA-I by MMP-8 may impair the first steps of reverse cholesterol transport, leading to increased accumulation of cholesterol in the vessel walls. Eventually, inhibition of MMPs by doxycycline may reduce the risk for atherosclerotic vascular diseases.
authors.affiliation: *Institute of Dentistry, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; National Institute for Health and Welfare, Public Health Genomics Unit, Biomedicum, Helsinki, Finland; Meilahti Clinical Proteomics Core Unit, Department of Biochemistry and Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Finland; and Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden aino.m.salminen@helsinki.fi.
authors.forename: Aino
authors.initials: A
authors.lastname: Salminen
authors.affiliation: *Institute of Dentistry, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; National Institute for Health and Welfare, Public Health Genomics Unit, Biomedicum, Helsinki, Finland; Meilahti Clinical Proteomics Core Unit, Department of Biochemistry and Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Finland; and Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Åström
authors.affiliation: *Institute of Dentistry, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; National Institute for Health and Welfare, Public Health Genomics Unit, Biomedicum, Helsinki, Finland; Meilahti Clinical Proteomics Core Unit, Department of Biochemistry and Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Finland; and Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Jari
authors.initials: J
authors.lastname: Metso
authors.affiliation: *Institute of Dentistry, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; National Institute for Health and Welfare, Public Health Genomics Unit, Biomedicum, Helsinki, Finland; Meilahti Clinical Proteomics Core Unit, Department of Biochemistry and Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Finland; and Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Rabah
authors.initials: R
authors.lastname: Soliymani
authors.affiliation: *Institute of Dentistry, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; National Institute for Health and Welfare, Public Health Genomics Unit, Biomedicum, Helsinki, Finland; Meilahti Clinical Proteomics Core Unit, Department of Biochemistry and Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Finland; and Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Tuula
authors.initials: T
authors.lastname: Salo
authors.affiliation: *Institute of Dentistry, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; National Institute for Health and Welfare, Public Health Genomics Unit, Biomedicum, Helsinki, Finland; Meilahti Clinical Proteomics Core Unit, Department of Biochemistry and Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Finland; and Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: *Institute of Dentistry, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; National Institute for Health and Welfare, Public Health Genomics Unit, Biomedicum, Helsinki, Finland; Meilahti Clinical Proteomics Core Unit, Department of Biochemistry and Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Finland; and Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Pirkko J
authors.initials: PJ
authors.lastname: Pussinen
authors.affiliation: *Institute of Dentistry, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; National Institute for Health and Welfare, Public Health Genomics Unit, Biomedicum, Helsinki, Finland; Meilahti Clinical Proteomics Core Unit, Department of Biochemistry and Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Finland; and Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Timo
authors.initials: T
authors.lastname: Sorsa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D001693:Biological Transport, Active; D002460:Cell Line; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014280:Triglycerides / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D010446:Peptide Fragments; D014280:Triglycerides; D002784:Cholesterol; C488762:MMP8 protein, human; C576328:MMP8 protein, mouse; D020784:Matrix Metalloproteinase 8
keywords: atherosclerosis; cholesterol metabolism; high-density lipoprotein; proteolytic enzyme