Cleavage of proteoglycans, plasma proteins and the platelet-derived growth factor receptor in the hemorrhagic process induced by snake venom metalloproteinases

Asega, Amanda F.; Menezes, Milene C.; Trevisan-Silva, Dilza; Cajado-Carvalho, Daniela; Bertholim, Luciana; Oliveira, Ana Karina de; Zelanis, André; Serrano, Solange M.T.

doi:10.1038/s41598-020-69396-y

Cited by 18 publications

(21 citation statements)

References 118 publications

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“…Hemorrhagic Factor 3 (HF3), a hemorrhagic P-III class SVMP from B. jararaca venom, cleaves in vivo endothelial glycocalyx proteoglycans such as biglycan, decorin, glypican-1, lumican and syndecan-1, participating to the disruption of microvasculature integrity and contributing to hemorrhage [143].…”

Section: Consequences On the Endotheliummentioning

confidence: 99%

Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

Larréché

Chippaux

Chevillard

et al. 2021

IJMS

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Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A2 and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood.

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Section: Consequences On the Endotheliummentioning

confidence: 99%

Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

Larréché

Chippaux

Chevillard

et al. 2021

IJMS

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“…cerastes ; this suggests that SVMPs and PLA 2 s are the main constituents of its venom. SVMPs are capable of damaging ECM components, such as proteoglycans [ 59 ], collagen, laminin, and fibronectin [ 60 ]. Thus, SVMPs are mainly involved in edema, inflammation, swelling, blistering, skin damage, tissue necrosis, myonecrosis, and cardiovascular shock.…”

Section: Main Species Responsible For Severe Envenomingsmentioning

confidence: 99%

Terrestrial venomous animals, the envenomings they cause, and treatment perspectives in the Middle East and North Africa

et al. 2021

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The Middle East and Northern Africa, collectively known as the MENA region, are inhabited by a plethora of venomous animals that cause up to 420,000 bites and stings each year. To understand the resultant health burden and the key variables affecting it, this review describes the epidemiology of snake, scorpion, and spider envenomings primarily based on heterogenous hospital data in the MENA region and the pathologies associated with their venoms. In addition, we discuss the venom composition and the key medically relevant toxins of these venomous animals, and, finally, the antivenoms that are currently in use to counteract them. Unlike Asia and sub-Saharan Africa, scorpion stings are significantly more common (approximately 350,000 cases/year) than snakebites (approximately 70,000 cases/year) and present the most significant contributor to the overall health burden of envenomings, with spider bites being negligible. However, this review also indicates that there is a substantial lack of high-quality envenoming data available for the MENA region, rendering many of these estimates speculative. Our understanding of the venoms and the toxins they contain is also incomplete, but already presents clear trends. For instance, the majority of snake venoms contain snake venom metalloproteinases, while sodium channel–binding toxins and potassium channel–binding toxins are the scorpion toxins that cause most health-related challenges. There also currently exist a plethora of antivenoms, yet only few are clinically validated, and their high cost and limited availability present a substantial health challenge. Yet, some of the insights presented in this review might help direct future research and policy efforts toward the appropriate prioritization of efforts and aid the development of future therapeutic solutions, such as next-generation antivenoms.

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“…The calculated molecular mass of the mature form of HF3 is 46 kDa, whereas on SDS-PAGE, it shows a mobility corresponding to a protein of ~70 kDa, indicating that it is heavily glycosylated [13,14]. HF3 was shown to degrade proteins of the plasma and extracellular matrix, including fibrinogen, fibronectin, vitronectin, von Willebrand factor, collagens IV and VI, laminin, matrigel, antithrombin III, complement components C3 and C4, prothrombin, and plasminogen in vitro [9,15]. Moreover, HF3 showed degradation or limited proteolysis of the proteoglycans aggrecan, brevican, biglycan, decorin, glypican-1, lumican, mimecan, and syndecan-1 [15].…”

Section: Introductionmentioning

confidence: 99%

“…HF3 was shown to degrade proteins of the plasma and extracellular matrix, including fibrinogen, fibronectin, vitronectin, von Willebrand factor, collagens IV and VI, laminin, matrigel, antithrombin III, complement components C3 and C4, prothrombin, and plasminogen in vitro [9,15]. Moreover, HF3 showed degradation or limited proteolysis of the proteoglycans aggrecan, brevican, biglycan, decorin, glypican-1, lumican, mimecan, and syndecan-1 [15]. Proteins extracted from the hemorrhagic dorsal skin of mice injected with HF3 were submitted to SDS-PAGE and immunostained with specific anti-proteoglycan antibodies, resulting in the demonstration of in vivo cleavage of biglycan, decorin, glypican-1, lumican, and syndecan-1 [15].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, HF3 showed degradation or limited proteolysis of the proteoglycans aggrecan, brevican, biglycan, decorin, glypican-1, lumican, mimecan, and syndecan-1 [15]. Proteins extracted from the hemorrhagic dorsal skin of mice injected with HF3 were submitted to SDS-PAGE and immunostained with specific anti-proteoglycan antibodies, resulting in the demonstration of in vivo cleavage of biglycan, decorin, glypican-1, lumican, and syndecan-1 [15]. Interestingly, HF3 cleaved the platelet derived growth factor receptor (PDGFR; alpha and beta), and PDGF, in vitro, and both receptor forms were also detected as degraded in vivo in the hemorrhagic process generated by HF3 in the mouse skin [15].…”

Section: Introductionmentioning

confidence: 99%

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Systemic Effects of Hemorrhagic Snake Venom Metalloproteinases: Untargeted Peptidomics to Explore the Pathodegradome of Plasma Proteins

Bertholim

Chaves

Oliveira

et al. 2021

Toxins

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Hemorrhage induced by snake venom metalloproteinases (SVMPs) is a complex phenomenon that involves capillary disruption and blood extravasation. HF3 (hemorrhagic factor 3) is an extremely hemorrhagic SVMP of Bothrops jararaca venom. Studies using proteomic approaches revealed targets of HF3 among intracellular and extracellular proteins. However, the role of the cleavage of plasma proteins in the context of the hemorrhage remains not fully understood. The main goal of this study was to analyze the degradome of HF3 in human plasma. For this purpose, approaches for the depletion of the most abundant proteins, and for the enrichment of low abundant proteins of human plasma, were used to minimize the dynamic range of protein concentration, in order to assess the proteolytic activity of HF3 on a wide spectrum of proteins, and to detect the degradation products using mass spectrometry-based untargeted peptidomics. The results revealed the hydrolysis products generated by HF3 and allowed the identification of cleavage sites. A total of 61 plasma proteins were identified as cleaved by HF3. Some of these proteins corroborate previous studies, and others are new HF3 targets, including proteins of the coagulation cascade, of the complement system, proteins acting on the modulation of inflammation, and plasma proteinase inhibitors. Overall, the data indicate that HF3 escapes inhibition and sculpts the plasma proteome by degrading key proteins and generating peptides that may act synergistically in the hemorrhagic process.

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Cleavage of proteoglycans, plasma proteins and the platelet-derived growth factor receptor in the hemorrhagic process induced by snake venom metalloproteinases

Cited by 18 publications

References 118 publications

Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

Terrestrial venomous animals, the envenomings they cause, and treatment perspectives in the Middle East and North Africa

Systemic Effects of Hemorrhagic Snake Venom Metalloproteinases: Untargeted Peptidomics to Explore the Pathodegradome of Plasma Proteins

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