Cleavage of proteoglycans, plasma proteins and the platelet-derived growth factor receptor in the hemorrhagic process induced by snake venom metalloproteinases

Autor(es)

Asega, Amanda F. . ^[1] ; Menezes, Milene C. ^[1] ; Trevisan-Silva, Dilza ^[1] ; Cajado-Carvalho, Daniela ^[1] ; Bertholim, Luciana ^[1] ; Oliveira, Ana K. ^{[1, 2]} ; Zelanis, Andre ^[3] ; Serrano, Solange M. T. ^[1]

Afiliação do(s) autor(es)

^[1] Inst Butantan, Ctr Toxins Immune Response & Cell Signaling CETIC, Lab Toxinol Aplicada, Av Vital Brasil 1500, BR-05503900 Sao Paulo, SP - Brazil

^[2] Ctr Nacl Pesquisa Energia & Mat CNPEM, Lab Nacl Biociencias LNBio, Campinas, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Ciencia & Tecnol, Sao Jose Dos Campos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 10, n. 1 JUL 31 2020.
• Citações Web of Science: 1

Resumo

Envenoming by viperid snakes results in a complex pattern of tissue damage, including hemorrhage, which in severe cases may lead to permanent sequelae. Snake venom metalloproteinases (SVMPs) are main players in this pathogenesis, acting synergistically upon different mammalian proteomes. Hemorrhagic Factor 3 (HF3), a P-III class SVMP from Bothrops jararaca, induces severe local hemorrhage at pmol doses in a murine model. Our hypothesis is that in a complex scenario of tissue damage, HF3 triggers proteolytic cascades by acting on a partially known substrate repertoire. Here, we focused on the hypothesis that different proteoglycans, plasma proteins, and the platelet derived growth factor receptor (PDGFR) could be involved in the HF3-induced hemorrhagic process. In surface plasmon resonance assays, various proteoglycans were demonstrated to interact with HF3, and their incubation with HF3 showed degradation or limited proteolysis. Likewise, Western blot analysis showed in vivo degradation of biglycan, decorin, glypican, lumican and syndecan in the HF3-induced hemorrhagic process. Moreover, antithrombin III, complement components C3 and C4, factor II and plasminogen were cleaved in vitro by HF3. Notably, HF3 cleaved PDGFR (alpha and beta) and PDGF in vitro, while both receptor forms were detected as cleaved in vivo in the hemorrhagic process induced by HF3. These findings outline the multifactorial character of SVMP-induced tissue damage, including the transient activation of tissue proteinases, and underscore for the first time that endothelial glycocalyx proteoglycans and PDGFR are targets of SVMPs in the disruption of microvasculature integrity and generation of hemorrhage. (AU)

• Processo FAPESP: 17/00715-0 - Enzimas proteolíticas de venenos de serpentes disparam cascatas de eventos moleculares ainda desconhecidos
• Beneficiário: Dilza Trevisan Silva
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 10/00206-0 - Caracterização molecular da hemorragia induzida pela metaloproteinase HF3: análise das interações com componentes da matriz extracelular, e da regeneração tecidual pós-hemorragia.
• Beneficiário: Amanda Francine Asega
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/19252-0 - Análise proteômica dos efeitos de PA-BJ, uma serinoproteinase do veneno de Bothrops jararaca, sobre cultura de células endoteliais de sangue periférico
• Beneficiário: Daniela Cajado de Oliveira Souza Carvalho
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 10/17328-0 - Caracterização proteômica comparativa da agregação plaquetária induzida pela trombina e pela PA-BJ, uma serinoproteinase do veneno da Bothrops jararaca.
• Beneficiário: Ana Karina de Oliveira
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 11/08514-8 - Estudo do degradoma do HF3, uma metaloproteinase hemorrágica da classe P-III do veneno da serpente Bothrops jararaca, sobre fibroblastos em cultura
• Beneficiário: André Zelanis Palitot Pereira
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/07467-1 - CeTICS - Centro de Toxinas, Imuno-Resposta e Sinalização Celular
• Beneficiário: Hugo Aguirre Armelin
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs