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Inhibition of protein kinase C βII isoform rescues glucose toxicity-induced cardiomyocyte contractile dysfunction: Role of mitochondria
- Wang, Zikuan, Zhang, Yanchun, Guo, Jingjing, Jin, Kuihua, Li, Jun, Guo, Xiaolan, Scott, Glenda I., Zheng, Qiangsun, Ren, Jun
- Life sciences 2013 v.93 no.2-3 pp. 116-124
- NAD(P)H oxidase (H2O2-forming), NADP (coenzyme), Western blotting, aconitate hydratase, adults, apoptosis, calcium, cardiomyocytes, cytotoxicity, diabetic complications, fluorescence, glucose, heart, hyperglycemia, image analysis, in vitro studies, mitochondria, oxidative stress, oxygen, protein kinase C, rats
- 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 PKCβII in glucose toxicity-induced cardiomyocyte contractile and intracellular Ca²⁺ aberrations. MAIN METHODS: Adult rat cardiomyocytes were maintained in normal (NG, 5.5mM) or high glucose (HG, 25.5mM) medium for 12h. 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/O₂ ⁻ 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 PKCβII inhibitor LY333531. Inhibition of PKCβII rescued glucose toxicity-induced generation of ROS and O₂ ⁻, apoptosis, cell death and mitochondrial injury (reduced aconitase activity, UCP-2 and PGC-1α). In vitro studies revealed that PKCβII 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 PKCβII isoform in the management of hyperglycemia-induced cardiac complications.