Inhibition of protein kinase C βII isoform rescues glucose toxicity-induced cardiomyocyte contractile dysfunction: Role of mitochondria

Aims: Hyperglycemia leads to cytotoxicity in the heart. Although theories were postulated for glucose toxicity-induced cardiomyocyte dysfunction including oxidative stress, the mechanism involved still remains unclear. Recent evidence has depicted a role of protein kinase C (PKC) in diabetic complications while high concentrations of glucose stimulate PKC. This study examined the role of PKC beta II in glucose toxicity-induced cardiomyocyte contractile and intracellular Ca2+ aberrations. Main methods: Adult rat cardiomyocytes were maintained in normal (NG, 5.5 mM) or high glucose (HG, 25.5 mM) medium for 12 h. Contractile and intracellular Ca2+ properties were measured using a video edge-detection system including peak shortening (PS), maximal velocity of shortening/relengthening (+/- dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), rise in intracellular Ca2+ Fura-2 fluorescence intensity and intracellular Ca2+ decay. Production of ROS/O-2(-) and mitochondrial integrity were examined using fluorescence imaging, aconitase activity and Western blotting. Key findings: High glucose triggered abnormal contractile and intracellular Ca2+ properties including reduced PS, +/- dL/dt, prolonged TR90, decreased electrically-stimulated rise in intracellular Ca2+ and delayed intracellular Ca2+ clearance, the effects of which were ablated by the PKC beta II inhibitor LY333531. Inhibition of PKC beta II rescued glucose toxicity-induced generation of ROS and O-2(-), apoptosis, cell death and mitochondrial injury (reduced aconitase activity, UCP-2 and PGC-1 alpha). In vitro studies revealed that PKC beta II inhibition-induced beneficial effects were mimicked by the NADPH oxidase inhibitor apocynin and were canceled off by mitochondrial uncoupling using FCCP. Significance: These findings suggest the therapeutic potential of specific inhibition of PKC beta II isoform in the management of hyperglycemia-induced cardiac complications. (C) 2013 Elsevier Inc. All rights reserved.