title: Tissue localization and extracellular matrix degradation by PI, PII and PIII snake venom metalloproteinases: clues on the mechanisms of venom-induced hemorrhage.
abstract: Snake venom hemorrhagic metalloproteinases (SVMPs) of the PI, PII and PIII classes were compared in terms of tissue localization and their ability to hydrolyze basement membrane components in vivo, as well as by a proteomics analysis of exudates collected in tissue injected with these enzymes. Immunohistochemical analyses of co-localization of these SVMPs with type IV collagen revealed that PII and PIII enzymes co-localized with type IV collagen in capillaries, arterioles and post-capillary venules to a higher extent than PI SVMP, which showed a more widespread distribution in the tissue. The patterns of hydrolysis by these three SVMPs of laminin, type VI collagen and nidogen in vivo greatly differ, whereas the three enzymes showed a similar pattern of degradation of type IV collagen, supporting the concept that hydrolysis of this component is critical for the destabilization of microvessel structure leading to hemorrhage. Proteomic analysis of wound exudate revealed similarities and differences between the action of the three SVMPs. Higher extent of proteolysis was observed for the PI enzyme regarding several extracellular matrix components and fibrinogen, whereas exudates from mice injected with PII and PIII SVMPs had higher amounts of some intracellular proteins. Our results provide novel clues for understanding the mechanisms by which SVMPs induce damage to the microvasculature and generate hemorrhage.
authors.affiliation: Instituto de Investigaciones Farmacéuticas, Facultad de Farmacia, Universidad de Costa Rica, San José, Costa Rica; Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: Cristina
authors.initials: C
authors.lastname: Herrera
authors.affiliation: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: Teresa
authors.initials: T
authors.lastname: Escalante
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Mathieu-Benoit
authors.initials: MB
authors.lastname: Voisin
authors.affiliation: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rucavado
authors.affiliation: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: Diego
authors.initials: D
authors.lastname: Morazán
authors.affiliation: University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Jéssica Kele A
authors.initials: JK
authors.lastname: Macêdo
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Calvete
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: Libia
authors.initials: L
authors.lastname: Sanz
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Sussan
authors.initials: S
authors.lastname: Nourshargh
authors.affiliation: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: José María
authors.initials: JM
authors.lastname: Gutiérrez
authors.affiliation: University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Fox
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism*; D006470:Hemorrhage / Q000139:chemically induced / Q000378:metabolism*; D006868:Hydrolysis; D007150:Immunohistochemistry; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D059748:Proteolysis; D040901:Proteomics; D012910:Snake Venoms / Q000201:enzymology*
chemical_list: D012910:Snake Venoms; D008666:Metalloendopeptidases; C069317:hemorrhagic metalloproteinase