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 .