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Toxins 2017, 9(8), 239; doi:10.3390/toxins9080239

Insights into the Mechanisms Involved in Strong Hemorrhage and Dermonecrosis Induced by Atroxlysin-Ia, a PI-Class Snake Venom Metalloproteinase

1
Programa de Pós-Graduação em Ciências-Toxinologia, Laboratório de Imunopatologia, Instituto Butantan, São Paulo 05503-900, Brazil
2
Laboratório de Imunopatologia, Instituto Butantan, São Paulo 05503-900, Brazil
3
Laboratório Especial de Toxinologia Aplicada, Center of Toxins, Immune-Response and Cell Signalig, CeTICS, Instituto Butantan, São Paulo 05503-900, Brazil
*
Author to whom correspondence should be addressed.
Academic Editor: Frank S. Markland
Received: 30 June 2017 / Revised: 28 July 2017 / Accepted: 29 July 2017 / Published: 2 August 2017
(This article belongs to the Section Animal Venoms)
View Full-Text   |   Download PDF [9558 KB, uploaded 2 August 2017]   |  

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. View Full-Text
Keywords: snake; venom; metalloproteinase; dermonecrosis; hemorrhage; Bothrops atrox; extracellular matrix snake; venom; metalloproteinase; dermonecrosis; hemorrhage; Bothrops atrox; extracellular matrix
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MDPI and ACS Style

Freitas-de-Sousa, L.A.; Colombini, M.; Lopes-Ferreira, M.; Serrano, S.M.T.; Moura-da-Silva, A.M. Insights into the Mechanisms Involved in Strong Hemorrhage and Dermonecrosis Induced by Atroxlysin-Ia, a PI-Class Snake Venom Metalloproteinase. Toxins 2017, 9, 239.

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