Abstract
Lys49-PLA2 myotoxins, an important component of various viperid snake venoms, are a class of PLA2-homolog proteins deprived of catalytic activity. Similar to enzymatically active PLA2 (Asp49) and to other classes of myotoxins, they cause severe myonecrosis. Moreover, these toxins are used as tools to study skeletal muscle repair and regeneration, a process that can be very limited after snakebites. In this work, the cytotoxic effect of different myotoxins, Bothrops asper Lys49 and Asp49-PLA2, Notechis scutatus notexin and Naja mossambica cardiotoxin, was evaluated on macrophages, cells that have a key role in muscle regeneration. Only the Lys49-myotoxin was found to trigger a rapid asynchronous death of mouse peritoneal macrophages and macrophagic cell lines through a process that involves ATP release, ATP-induced ATP release and that is inhibited by various purinergic receptor antagonists. ATP leakage is induced also at sublytical doses of the Lys49-myotoxin, it involves Ca2+ release from intracellular stores, and is reduced by inhibitors of VSOR and the maxi-anion channel. The toxin-induced cell death is different from that caused by high concentration of ATP and appears to be linked to localized purinergic signaling. Based on present findings, a mechanism of cell death is proposed that can be extended to other cytolytic proteins and peptides.
Highlights
Myotoxins are the main snake venom components causing tissue necrosis and, upon injection into higher animals, they cause irreversible damage on skeletal muscle fibers
The pathology caused by cardiotoxins and PLA2 myotoxins develops rapidly and it is associated with marked damage to the sarcolemma, whereas pathology associated with ‘small’ myotoxins has a more delayed onset and sarcolemma damage is not apparent.[6]
Mt-I, Mt-II, Ntx and cardiotoxin of Naja mossambica (Ctx) activities were evaluated on isolated peritoneal mouse macrophages
Summary
Myotoxins are the main snake venom components causing tissue necrosis and, upon injection into higher animals, they cause irreversible damage on skeletal muscle fibers. Mt-II was found to induce an initial ATP release, followed by an ATP-induced ATP release, that participates in the onset of a rapid and asynchronous cell burst This is a novel type of cell death, quite different from that induced by a massive extracellular addition of ATP in J774.A1 and N13 mouse macrophagic cell lines.[13,14]. Based on these data, a two-step model of Mt-II-induced cytotoxicity is proposed, with an initial alteration of the plasma membrane associated with purinergic signaling followed by cytolysis due to the insertion of the toxin into the lipid bilayer
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