Redox-driven antiplatelet effect of snake venom phospholipase A2: VLPLA2 from Vipera lebetina venom as a new antithrombotic agent

BACKGROUND: Snake venom phospholipases A2 are multifunctional enzymes which modulate haemostatic balance. Their antithrombotic potential via redox-sensitive signalling pathways remains underexplored. OBJECTIVES: This study reports the redox-mediated antiplatelet effects of vipera l ebetina phospholipase A2 (VLPLA2), a phospholipase A2 purified from Vipera lebetina, we also assess its potential as a novel antithrombotic agent. METHODOLOGY: VLPLA2 was evaluated for its effects on human platelet aggregation, redox signalling pathways and antioxidant enzyme modulation. The involvement of VLPLA2 in platelet adhesion to fibrinogen was also investigated. RESULTS: VLPLA2 strongly inhibited ADP-induced platelet aggregation and platelet adhesion to fibrinogen, probably by increasing catalase activity and reducing hydrogen peroxide levels, suggesting a compensatory redox response. The antiplatelet effect of VLPLA2 appears to be mediated by ROS overproduction, possibly via the involvement of nicotinamide adenine dinucleotide reduced phosphate (NADPH) oxidase signalling pathways. This redox imbalance leads to oxidative modifications of P2Y12 ADP receptor and GPIIb/IIIa fibrinogen receptor, consequently, avoiding their activation. CONCLUSIONS: Our data reveal a dual mechanism of VLPLA2 via enzymatic membrane phospholipid hydrolysis and oxidative modulation of platelet signalling pathways. VLPLA2 could be a promising candidate for the development of redox-targeted antithrombotic therapeutics.