title: Toll-like receptor 2 activation and serum amyloid A regulate smooth muscle cell extracellular matrix.
abstract: Smooth muscle cells contribute to extracellular matrix remodeling during atherogenesis. De-differentiated, synthetic smooth muscle cells are involved in processes of migration, proliferation and changes in expression of extracellular matrix components, all of which contribute to loss of homeostasis accompanying atherogenesis. Elevated levels of acute phase proteins, including serum amyloid A (SAA), are associated with an increased risk for atherosclerosis. Although infection with periodontal and respiratory pathogens via activation of inflammatory cell Toll-like receptor (TLR)2 has been linked to vascular disease, little is known about smooth muscle cell TLR2 in atherosclerosis. This study addresses the role of SAA and TLR2 activation on smooth muscle cell matrix gene expression and insoluble elastin accumulation. Cultured rat aortic smooth muscle cells were treated with SAA or TLR2 agonists and the effect on expression of matrix metallopeptidase 9 (MMP9) and tropoelastin studied. SAA up-regulated MMP9 expression. Tropoelastin is an MMP9 substrate and decreased tropoelastin levels in SAA-treated cells supported the concept of extracellular matrix remodeling. Interestingly, SAA-induced down-regulation of tropoelastin was not only evident at the protein level but at the level of gene transcription as well. Contributions of proteasomes, nuclear factor κ B and CCAAT/enhancer binding protein β on regulation of MMP9 vs. tropoleastin expression were revealed. Effects on Mmp9 and Eln mRNA expression persisted with long-term SAA treatment, resulting in decreased insoluble elastin accumulation. Interestingly, the SAA effects were TLR2-dependent and TLR2 activation by bacterial ligands also induced MMP9 expression and decreased tropoelastin expression. These data reveal a novel mechanism whereby SAA and/or infection induce changes in vascular elastin consistent with atherosclerosis.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Seidl
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Pessolano
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bishop
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Best
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Celeste B
authors.initials: CB
authors.lastname: Rich
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Stone
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Barbara M
authors.identifier: http://orcid.org/0000-0001-8560-4249
authors.initials: BM
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012307:Risk Factors; D000685:Serum Amyloid A Protein / Q000008:administration & dosage / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D014333:Tropoelastin / Q000235:genetics*
chemical_list: D000685:Serum Amyloid A Protein; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014333:Tropoelastin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9