A Novel Mediator of MPO (Myeloperoxidase)-Induced Endothelial Dysfunction
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See related article, pp 761–770
MPO (myeloperoxidase) is released from cytoplasmic granules of neutrophils, monocytes, and macrophages.1 MPO uses hydrogen peroxide as a substrate to generate reactive species that oxidize a variety of molecules, contributing to tissue injury and damage.1,2 In addition, MPO-generated products have microbicidal activity, playing an important role in host defense.1 The multiple and opposing properties of MPO pose difficulties in the development of therapeutic strategies that target this enzyme.
In the current issue of Hypertension, Etwebi et al3 propose a paradigm that focuses on the endothelial actions of MPO, and thus, it may not compromise its host defense effects. Specifically, these authors suggest that signaling molecules, which are located in endothelial cells downstream of MPO, can provide novel targets for the treatment of MPO-induced endothelial dysfunction and inflammation. Using pharmacological tools and genetically modified mice, Etwebi et al identify, for first time, calpain and its modulators as novel pharmacological targets downstream of MPO. They demonstrate that MPO reduces phosphorylation of eNOS (endothelial NO synthase) at serine 1147, causing a reduction in NO production, which consequently increases calpain activity by reducing its nitrosylation. Increased activity of calpain then leads to PP2A (protein phosphatase 2A)- and AMPK (5′ adenosine monophosphate-activated protein kinase)-dependent reduction in eNOS phosphorylation. This last event results in a decrease in NO generation and subsequent augmentation of calpain activity (Figure).