A Comprehensive View of the Structural and Functional Alterations of Extracellular Matrix by Snake Venom Metalloproteinases (SVMPs): Novel Perspectives on the Pathophysiology of Envenoming

Abstract

Snake venom metalloproteinases (SVMPs) affect the extracellular matrix (ECM) in multiple and complex ways. Previously, the combination of various methodological platforms, including electron microscopy, histochemistry, immunohistochemistry, and Western blot, has allowed a partial understanding of such complex pathology. In recent years, the proteomics analysis of exudates collected in the vicinity of tissues affected by SVMPs has provided novel and exciting information on SVMP-induced ECM alterations. The presence of fragments of an array of ECM proteins, including those of the basement membrane, has revealed a complex pathological scenario caused by the direct action of SVMPs. In addition, the time-course analysis of these changes has underscored that degradation of some fibrillar collagens is likely to depend on the action of endogenous proteinases, such as matrix metalloproteinases (MMPs), synthesized as a consequence of the inflammatory process. The action of SVMPs on the ECM also results in the release of ECM-derived biologically-active peptides that exert diverse actions in the tissue, some of which might be associated with reparative events or with further tissue damage. The study of the effects of SVMP on the ECM is an open field of research which may bring a renewed understanding of snake venom-induced pathology.

Snake C-Type Lectins Potentially Contribute to the Prey Immobilization in Protobothrops mucrosquamatus and Trimeresurus stejnegeri Venoms

“…It is worth noting that the purified mucetin and stejnulxin showed a stronger ability to aggregate thrombocytes/platelets than the crude venoms in vitro, as shown in Figure 4, but they are comparable with the crude venoms in animal experiments at the same concentration, as shown in Figures 1-3. This is probably because crude viper venoms may contain components such as metalloproteinases and hyaluronidase that favor the spread of the snaclecs in the tissue and in the circulatory system [27]. Alternately, there may also be unknown factors in the crude venoms that are helpful for prey immobilization via inducing cardiovascular collapse and prolonged hypotension [28].…”

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

“…One of the ubiquitous weapons in venom is metalloproteases [41]. These enzymes attack basement membranes and collagen in tissues to increase venom spread and disrupt blood vessels [14].…”

“…In addition, these bioactive peptides increase venom toxicity by triggering and amplifying inflammation [15]. Further, they induce the transcription and translation of endogenous matrix metalloproteases that attack types of collagen that are outside the range of svMPs [41].…”

“…It is generally accepted that metalloproteases in snake venoms play central roles in hemorrhage, by loosening the connective tissue components responsible for blood vessel structural integrity [41]. The pioneering histologic studies of McKay and Owenby [73,74] described destruction of basement membranes of capillaries in tissues exposed to hemorrhagic venom components, actions now thought primarily to be mediated by these metalloprotease enzymes.…”

“…The ability of svMPs to degrade various types of extracellular matrix proteins has been demonstrated in vitro by protein electrophoresis and immunoblot techniques, allowing visualization of digestion fragments. svMPs hydrolyze laminin, nidogen, enactin, type IV collagen, fibronectin, and proteoglycans (for review see [41]). A recent proteomic analysis revealed an even greater range of protein targets [75].…”