MLKL triggers NLRP3 activation in sodium arsenite-induced myocardial necroinflammation.

Prolonged exposure to arsenic elevates the risk of developing a range of cardiovascular disorders. However, the mechanisms underlying myocardial damage from arsenic exposure remain elusive. Our earlier research suggest that drinking arsenic-contaminated water can lead to substantial inflammatory and necrotic injury in the myocardium of rats. This study was to ascertain whether mixed lineage kinase domain-like protein (MLKL) triggers Nod-like receptor protein-3 (NLRP3) activation during arsenic-induced myocardial necroinflammation in H9C2 cardiomyocytes and Mlkl knockout C57BL/6 mice. We demonstrated that arsenic exposure induces necroptosis by activating the receptor-interacting serine/threonine-protein kinase-3 (RIPK3)/MLKL pathway in vivo and in vitro. Consistent with our hypotheses, we found that necroptosis inhibitors (RIPK1 inhibitor necrostatin-1 [Nec-1], RIPK3 inhibitor [GSK-872], MLKL inhibitor [NSA]) and Mlkl genetic knockout can partially protect against arsenic-induced inflammatory damage. Additionally, these strategies can downregulate the expression of key proteins associated with the activation of the NLRP3 inflammasome, including NLRP3, Caspase-1, and interleukin-1β (IL-1β). Taken together, our findings demonstrate that MLKL triggers NLRP3 inflammasome activation and plays an essential role in arsenic-induced myocardial necroinflammation.