Jararhagin is a 52 kDa hemorrhagic P-III
metalloproteinase isolated from the
venom of the medically important Brazilian pit-viper Bothrops jararaca. It is a member of the reprolysin family of
zinc metalloproteinases containing a catalytic
metalloproteinase domain followed by a
disintegrin-like and a
cysteine-rich domain. The impact of
jararhagin on hemostasis has been extensively studied using in vitro and in vivo model systems as well as in clinical studies.
Jararhagin-induced
hemorrhage is the result of the degradation of sub-endothelial matrix
proteins leading to the disruption of the blood vessel endothelium, with accompanying disturbances in platelet function. The versatility of
jararhagin is further demonstrated by its direct action on
von Willebrand factor, the degradation of
fibrinogen, by its inhibition of platelet adhesion to
collagen and by its inability to be affected by the plasma inhibitor alpha(2)-macroglobulin.
Collagen-induced platelet aggregation is inhibited by
jararhagin though the binding of the molecule to the alpha(2) subunit I domain of the platelet surface alpha(2)beta(1)
integrin (
collagen receptor).
Jararhagin also cleaves the beta(1) subunit of the same
integrin, inhibiting platelet interaction and ultimately causing impairment of signal transduction. The effect of
jararhagin on cell systems other than platelets is evaluated; in fibroblasts,
jararhagin functions as a
collagen-mimetic substrate and, in endothelial cells, it causes apoptosis and indirectly inhibits cell proliferation by release of
angiostatin-like compounds.
Jararhagin induces a strong pro-inflammatory response characterized by intense leukocyte accumulation at the site of the injection. Although
hemorrhage and
edema are a response to the direct effect of
jararhagin,
jararhagin-induced
inflammation and
necrosis are dependent on macrophages and key pro-inflammatory
cytokines or their receptors. Some data also indicate that the toxin possesses anti-tumorgenic properties. Methods for inhibiting
jararhagin are reviewed; this encompasses the use of synthetic
peptides to the isolation of naturally occurring mammalian
peptides and the development of toxin-specific
antibodies through
DNA immunisation and
monoclonal antibody technologies. The availability of
jararhagin makes it an important tool for research into the mechanisms of action of similar toxins, for insights into cellular interactions and for clinical investigations into the treatment of envenomings from B. jararaca.