Endothelial NOS-dependent activation of c-Jun NH2-terminal kinase by oxidized low-density lipoprotein

Oxidized low-density lipoprotein (oxLDL) is known to activate a number of s ignal transduction pathways in endothelial cells. Among these are the c-Jun NH2-terminal kinase (JNK), also known as stress-activated protein kinase, and extracellular signal-regulated kinase (ERK). These mitogen-activated pr otein kinases (MAP kinase) determine cell survival in response to environme ntal stress. Interestingly, JNK signaling involves redox-sensitive mechanis ms and is activated by reactive oxygen and nitrogen species derived from bo th NADPH oxidases, nitric oxide synthases (NOS), peroxides, and oxidized lo w-density lipoprotein (oxLDL). The role of endothelial NOS (eNOS) in the ac tivation of JNK in response to oxLDL has not been examined. Herein, we show that on exposure of endothelial cells to oxLDL, both ERK and JNK are activ ated through independent signal transduction pathways. A key role of eNOS a ctivation through a phosphatidylinositol-3-kinase-dependent mechanism leadi ng to phosphorylation of eNOS is demonstrated for oxLDL-dependent activatio n of JNK. Moreover, we show that activation of ERK by oxLDL is critical in protection against the cytotoxicity of oxLDL.