Abstract 458: Chronic Inhibition of Protein Kinase C Improves Coronary Endothelial Function in the Setting of Diabetes and Hypoxia

Abstract

Background: Both Diabetes (DM) and hypoxia/re-oxygenation (H/R) upregulate protein kinase C (PKC), resulting in coronary endothelial dysfunction. We hypothesized that chronic inhibition of PKC protects coronary endothelial function against DM and H/R injury. Methods: Genetically modified obesity and type-2 diabetic mice (female) were orally treated with or without selective PKCα/β inhibitor ruboxistaurin (10μg/g) for 4 weeks (n = 6/group). Coronary small arteries (70-110 μm in diameter) were then dissected from the harvested heart of mice. The isolated vessels were subjected to 60-min of hyperkalemic cardioplegic hypoxia (15°C) and then reperfused with oxygenated Krebs-Henseleit buffer for 60 minutes. At the end of 60-min re-oxygenation, all vessels was pretreated with endothelin-1 and then the responses to endothelium-dependent vasodilators, adenosine-diphosphate (ADP) and substance P were examined. Results: PKCα/β inhibition significantly improved the recovery of coronary endothelial function in the small coronary arteries of diabetic mice showing increased relaxation response to ADP and substance P in dose-dependent manner compared with the DM control (no-pretreatment alone) (*p<0.05). Conclusion: Chronic inhibition of PKC significantly improved the recovery of coronary endothelial function against a period of cardiolpegic H/R in the diabetic microvasculature. These data suggest that the PKC inhibitor ruboxistaurin represents a novel potential therapeutic for coronary endothelial dysfunctionin patients with DM following cardioplegic ischemia and reperfusion.