title: Inhibition of protein kinase C βII isoform rescues glucose toxicity-induced cardiomyocyte contractile dysfunction: role of mitochondria.
abstract: OBJECTIVE
  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 Ca(2+) aberrations.
  
  
  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 Ca(2+) 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 Ca(2+) Fura-2 fluorescence intensity and intracellular Ca(2+) decay. Production of ROS/O2(-) and mitochondrial integrity were examined using fluorescence imaging, aconitase activity and Western blotting.
  
  
  RESULTS
  High glucose triggered abnormal contractile and intracellular Ca(2+) properties including reduced PS, ±dL/dt, prolonged TR90, decreased electrically-stimulated rise in intracellular Ca(2+) and delayed intracellular Ca(2+) 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.
  
  
  CONCLUSIONS
  These findings suggest the therapeutic potential of specific inhibition of PKCβII isoform in the management of hyperglycemia-induced cardiac complications.
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Zikuan
authors.initials: Z
authors.lastname: Wang
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Guo
authors.forename: Kuihua
authors.initials: K
authors.lastname: Jin
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Guo
authors.forename: Glenda I
authors.initials: GI
authors.lastname: Scott
authors.forename: Qiangsun
authors.initials: Q
authors.lastname: Zheng
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D005947:Glucose / Q000633:toxicity*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C099154:ruboxistaurin; D019255:NADPH Oxidases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D000154:Aconitate Hydratase; D005947:Glucose; D002118:Calcium
keywords: Cardiomyocytes; Contractile function; Glucose toxicity; Protein kinase C isoform