Modulating myeloperoxidase‐induced endothelial damage by a carbon monoxide‐releasing molecule, CORM‐3 (146.9)

Previous work has demonstrated that carbon monoxide releasing molecules (CORMs) suppress inflammation, however, the mechanisms are not well understood. Neutrophil (PMN)‐derived myeloperoxidase (MPO) is known to play a significant role in the pathophysiology of numerous inflammatory disorders through: 1) direct peroxidation and 2) producing hypohalous acids, (e.g. hypochlorous acid). Thus, an overwhelming MPO‐dependent production of oxidants in the sub‐endothelial space after PMN degranulation, contributes to tissue damage and propagating inflammation. We hypothesized that CORM‐3 interferes with MPO’s catalytic activity, and thereby mitigates endothelial inflammatory damage. In vitro assays were used to study MPO catalytic activity inhibition. Further, live cell in vitro assays were used to investigate endothelial damage through measuring reactive oxygen species (ROS) and cellular permeability. Our results indicate that CORM‐3 inhibits total MPO activity as well as MPO’s peroxidation and halogenation cycles. Cellular assays determined that ROS production and cellular permeability are decreased when extracellular MPO is treated with CORM‐3. In all assays inactivated CORM‐3 (iCORM‐3) was significantly less effective than CORM‐3. We conclude that CORM‐3 may mitigate inflammatory damage partly through inhibiting MPO activity. Grant Funding Source : Supported by Heart and Stroke Foundation, HSFO‐393 and LHRI IRF‐025‐09