Abstract
Hemorrhage is the most prominent effect of snake venom metalloproteinases (SVMPs) in human envenomation. The capillary injury is a multifactorial effect caused by hydrolysis of the components of the basement membrane (BM). The PI and PIII classes of SVMPs are abundant in viperid venoms and hydrolyze BM components. However, hemorrhage is associated mostly with PIII-class SVMPs that contain non-catalytic domains responsible for the binding of SVMPs to BM proteins, facilitating enzyme accumulation in the tissue and enhancing its catalytic efficiency. Here we report on Atroxlysin-Ia, a PI-class SVMP that induces hemorrhagic lesions in levels comparable to those induced by Batroxrhagin (PIII-class), and a unique SVMP effect characterized by the rapid onset of dermonecrotic lesions. Atroxlysin-Ia was purified from B. atrox venom, and sequence analyses indicated that it is devoid of non-catalytic domains and unable to bind to BM proteins as collagen IV and laminin in vitro or in vivo. The presence of Atroxlysin-Ia was diffuse in mice skin, and localized mainly in the epidermis with no co-localization with BM components. Nevertheless, the skin lesions induced by Atroxlysin-Ia were comparable to those induced by Batroxrhagin, with induction of leukocyte infiltrates and hemorrhagic areas soon after toxin injection. Detachment of the epidermis was more intense in skin injected with Atroxlysin-Ia. Comparing the catalytic activity of both toxins, Batroxrhagin was more active in the hydrolysis of a peptide substrate while Atroxlysin-Ia hydrolyzed more efficiently fibrin, laminin, collagen IV and nidogen. Thus, the results suggest that Atroxlysin-Ia bypasses the binding step to BM proteins, essential for hemorrhagic lesions induced by PII- and P-III class SVMPs, causing a significantly fast onset of hemorrhage and dermonecrosis, due to its higher proteolytic capacity on BM components.
Highlights
Many pathological effects caused by snakes of the genus Bothrops in human envenomings are related to the direct or indirect activity of snake venom metalloproteinases (SVMPs), such as Toxins 2017, 9, 239; doi:10.3390/toxins9080239 www.mdpi.com/journal/toxinsToxins 2017, 9, 239 hemorrhage [1], skeletal muscle necrosis [2], skin damage [3,4], inhibition of platelet aggregation and coagulopathies [5], edema and inflammatory reactions [6,7,8]
Considering Atroxlysin-Ia high hemorrhagic activity and its ability to induce dermonecrosis, we proceeded Atroxlysin-Ia to the investigation of mechanisms involved thesetoeffects comparing the Considering high hemorrhagic activity and itsin ability induceby dermonecrosis, we morphological alterations induced by Atroxlysin-Ia and Because hemorrhage and proceeded to the investigation of mechanisms involved in these effects by comparing the skin damage induced by Atroxlysin-Ia are effects ofand rapid onset, we selected the time of 20 min morphological alterations induced by Atroxlysin-Ia
In this paper we describe unique activities of a PI-class SVMP isolated from Bothrops atrox venom, Atroxlysin-Ia, that induces strong hemorrhage and dermonecrosis in the skin of mice
Summary
Many pathological effects caused by snakes of the genus Bothrops in human envenomings are related to the direct or indirect activity of snake venom metalloproteinases (SVMPs), such as Toxins 2017, 9, 239; doi:10.3390/toxins9080239 www.mdpi.com/journal/toxinsToxins 2017, 9, 239 hemorrhage [1], skeletal muscle necrosis [2], skin damage [3,4], inhibition of platelet aggregation and coagulopathies [5], edema and inflammatory reactions [6,7,8]. SVMPs are zinc-dependent multi-domain proteins, which have been classified in three classes according to their domain composition in mature form. Hemorrhage is a very important effect induced by SVMPs and is directly correlated to the hydrolysis of the basement membrane (BM) proteins from micro vessels [10,11,12]. Three factors are important for this effect: the binding of the enzymes to the BM components of the capillaries [11]; the localization at BM enhancing the hydrolysis of BM and cell proteins involved in capillary stability and cell anchorage [13]; and the hemodynamic forces within the microcirculation contribute to the distension and rupture of the capillary wall, with consequent hemorrhage [10]
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