title: MMP-9-Dependent Serum-Borne Bioactivity Caused by Multiwalled Carbon Nanotube Exposure Induces Vascular Dysfunction via the CD36 Scavenger Receptor.
abstract: Inhalation of multiwalled carbon nanotubes (MWCNT) causes systemic effects including vascular inflammation, endothelial dysfunction, and acute phase protein expression. MWCNTs translocate only minimally beyond the lungs, thus cardiovascular effects thereof may be caused by generation of secondary biomolecular factors from MWCNT-pulmonary interactions that spill over into the systemic circulation. Therefore, we hypothesized that induced matrix metalloproteinase-9 (MMP-9) is a generator of factors that, in turn, drive vascular effects through ligand-receptor interactions with the multiligand pattern recognition receptor, CD36. To test this, wildtype (WT; C57BL/6) and MMP-9(-/-)mice were exposed to varying doses (10 or 40 µg) of MWCNTs via oropharyngeal aspiration and serum was collected at 4 and 24 h postexposure. Endothelial cells treated with serum from MWCNT-exposed WT mice exhibited significantly reduced nitric oxide (NO) generation, as measured by electron paramagnetic resonance, an effect that was independent of NO scavenging. Serum from MWCNT-exposed WT mice inhibited acetylcholine (ACh)-mediated relaxation of aortic rings at both time points. Absence of CD36 on the aortic rings (obtained from CD36-deficient mice) abolished the serum-induced impairment of vasorelaxation. MWCNT exposure induced MMP-9 protein levels in both bronchoalveolar lavage and whole lung lysates. Serum from MMP-9(-/-)mice exposed to MWCNT did not diminish the magnitude of vasorelaxation in naïve WT aortic rings, although a modest right shift of the ACh dose-response curve was observed in both MWCNT dose groups relative to controls. In conclusion, pulmonary exposure to MWCNT leads to elevated MMP-9 levels and MMP-9-dependent generation of circulating bioactive factors that promote endothelial dysfunction and decreased NO bioavailability via interaction with vascular CD36.
authors.affiliation: *Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131.
authors.forename: Mario
authors.initials: M
authors.lastname: Aragon
authors.affiliation: National Institute for Occupational Safety and Health, Morgantown, West Virginia 26508;
authors.forename: Aaron
authors.initials: A
authors.lastname: Erdely
authors.affiliation: National Institute for Occupational Safety and Health, Morgantown, West Virginia 26508;
authors.forename: Lindsey
authors.initials: L
authors.lastname: Bishop
authors.affiliation: National Institute for Occupational Safety and Health, Morgantown, West Virginia 26508;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Salmen
authors.affiliation: *Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131.
authors.forename: John
authors.initials: J
authors.lastname: Weaver
authors.affiliation: *Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131.
authors.forename: Jim
authors.initials: J
authors.lastname: Liu
authors.affiliation: *Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131.
authors.forename: Pamela
authors.initials: P
authors.lastname: Hall
authors.affiliation: National Institute for Occupational Safety and Health, Morgantown, West Virginia 26508;
authors.forename: Tracy
authors.initials: T
authors.lastname: Eye
authors.affiliation: National Institute for Occupational Safety and Health, Morgantown, West Virginia 26508;
authors.forename: Vamsi
authors.initials: V
authors.lastname: Kodali
authors.affiliation: National Institute for Occupational Safety and Health, Morgantown, West Virginia 26508;
authors.forename: Patti
authors.initials: P
authors.lastname: Zeidler-Erdely
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298.
authors.forename: Jillian E
authors.initials: JE
authors.lastname: Stafflinger
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Ottens
authors.affiliation: *Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131 mcampen@unm.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Campen
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D037742:Nanotubes, Carbon / Q000633:toxicity*; D009569:Nitric Oxide / Q000097:blood; D044967:Serum / Q000737:chemistry / Q000276:immunology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D018955:CD36 Antigens; D037742:Nanotubes, Carbon; D009569:Nitric Oxide; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: CD36; MMP-9.; carbon nanoparticle; cardiovascular; serum; toxicity; vascular