The potential clinical application of protein kinase C beta II peptide inhibitor or Gö 6983 in vascular endothelial dysfunction
Vascular endothelial dysfunction which is associated with increased oxidative stress and decreased endothelial-derived nitric oxide has been considered as a major initial event in various diseases, such as atherosclerosis, diabetes and ischemia/reperfusion (I/R) injury. Previously we found that a broad-spectrum protein kinase C (PKC) inhibitor (i.e., Gö 6983) and a specific PKC beta II peptide inhibitor (PKC ßII-) were cardioprotective in myocardial I/R injury. However, the direct effects of Gö6983 or PKC ßII- on vascular endothelial dysfunction and the related leukocyte-endothelial interactions are still unclear. The leukocyte rolling, adherence and transmigration were estimated by using intravital microscopy in rat mesenteric postcapillary venules. We found that superfusion of NG -nitro-L-arginine-methyl-ester (L-NAME, 50 µM) induced endothelial dysfunction and significantly increased leukocyte-endothelial interactions within a 2 hour period compared to Krebs' buffer control group (P<0.05). By contrast, Gö6983 (25 nM-200 nM) or PKC ßII- (0.1 µM-10 µM) dose-dependently attenuated these interactions induced by L-NAME (P<0.05). Moreover, histological evaluation of Gö 6983 (200 nM) or PKC ßII- (10 µM) superfused mesenteric tissue exhibited significantly less leukocyte adherence and tissue transmigration, as well as significantly less intercellular adhesion molecule-1 expression compared to L-NAME group. Finally, in a rat extracorporeal shock wave lithotripsy model, we demonstrated that PKC ßII- (0.055-0.55 mg/kg) significantly decreased oxidative stress when hydrogen peroxide was measured directly from rat renal veins (P<0.05). In summary, Gö 6983 or PKC ßII- can decrease the proinflammatory responses in vascular endothelium and may provide a potential clinical treatment to prevent vascular endothelial dysfunction.
Current Topics in Pharmacology
Chen, Qian; Rueter, Brian; Krass, Samuel; Zambrano, Christopher; Thomas, Shawn; Prince, Catherine; Bell, Brandon; Chai, Vincent; Emrich, Jeffery; and Young, Lindon, "The potential clinical application of protein kinase C beta II peptide inhibitor or Gö 6983 in vascular endothelial dysfunction" (2010). PCOM Scholarly Papers. 453.