The Effects of Protein Kinase C (PKC) Epsilon Peptide Regulation on Endothelial Nitric Oxide Synthase (eNOS) Uncoupling on Leukocyte-Endothelial Interactions in Rat Mesenteric Postcapillary Venules

摘要

Endotheiial-derived nitric oxide (NO) is essential in the regulation of blood pressure and promotes an antithrombotic surface which attenuates leukocyte-endothelial interactions associated with vascular injury. eNOS produces NO from L-arginine in the presence of essential cofactor tetrahydrobiopterin (BH4). When BH4 is oxidized to dihydrobiopterin (BH2), the ratio of BH2/BH4 is increased during vascular injury and promotes eNOS uncoupling, causing eNOS to produce superoxide (SO) instead of NO [1]. However, the role of BH2 to induce eNOS uncoupling and promote leukocyte-endothelial interactions in mesenteric circulation has no1 been characterized in vivo. Moreover, the role of compounds that can increase or decrease eNOS activity in the presence of an increased BH2/BH4 ratio has yet to be determined. PKC epsilon (PKC ε) positively regulates eNOS activity via phosphorylation of serine 1177. Cell-permeable myristoylated (Myr) PKC e peptide activator (PKC e+) or inhibitor (PKC s-) are known to increase or decrease NO release in vitro, respectively [2]. The effect of PKC ε+ is known to be inhibited with classical NOS inhibitors, such as N~G -nitro-L-arginine methyl estet (L-NAME). However, the effect of PKC ε+ or PKC ε- to exacerbate or attenuate BH2-inducec leukocyte-endothelial interactions has not yet been determined.