biostudies-literatureNigro PNHLBI NIH HHS1971-9https://www.ebi.ac.uk/biostudies/studies/S-EPMC3173991biostudies-literatureUnknown116(11)PKCζ has emerged as a pathologic mediator of endothelial cell dysfunction, based on its essential role in tumor necrosis factor α (TNFα)-mediated inflammation. In contrast, extracellular signal-regulated kinase 5 (ERK5) function is required for endothelial cell homeostasis as shown by activation of Krüppel-like factor 2 (KLF2), increased endothelial nitric-oxide synthase (eNOS) expression, and inhibition of apoptosis. We hypothesized that protein kinase C ζ (PKCζ) activation by TNFα would inhibit the ERK5/KLF2/eNOS pathway. TNFα inhibited the steady laminar flow-induced eNOS expression, and this effect was reversed by the dominant-negative form of PKCζ (Ad.DN-PKCζ). In addition, ERK5 function was inhibited by either TNFα or the transfection of the catalytic domain of PKCζ. This inhibition BloodPKCzeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5.PMC3173991R01 HL088637P01 HL077789-05HL-064839P01 HL077789HL-077789R01 HL102746HL-088637R01 HL064839R01 HL064839-10Fujiwara KLi JDMcClain CLim JHHeo KSBerk BCNigro PWoo CHLee HSatoh KAbe JO'Dell MRfalsePKCzeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5.PKCζ has emerged as a pathologic mediator of endothelial cell dysfunction, based on its essential role in tumor necrosis factor α (TNFα)-mediated inflammation. In contrast, extracellular signal-regulated kinase 5 (ERK5) function is required for endothelial cell homeostasis as shown by activation of Krüppel-like factor 2 (KLF2), increased endothelial nitric-oxide synthase (eNOS) expression, and inhibition of apoptosis. We hypothesized that protein kinase C ζ (PKCζ) activation by TNFα would inhibit the ERK5/KLF2/eNOS pathway. TNFα inhibited the steady laminar flow-induced eNOS expression, and this effect was reversed by the dominant-negative form of PKCζ (Ad.DN-PKCζ). In addition, ERK5 function was inhibited by either TNFα or the transfection of the catalytic domain of PKCζ. This inhibition 2010-01-01T00:00:00Z2010 Sep2025-05-29T22:12:02.32Z2025-05-29T22:12:02.32ZS-EPMC31739912053879910.1182/blood-2010-02-269134