title: Inhibition of protein kinase C βII isoform ameliorates methylglyoxal advanced glycation endproduct-induced cardiomyocyte contractile dysfunction.
abstract: OBJECTIVE
  Accumulation of advanced glycation endproduct (AGE) contributes to diabetic complication including diabetic cardiomyopathy although the precise underlying mechanism still remains elusive. Recent evidence depicted a pivotal role of protein kinase C (PKC) in diabetic complications. To this end, this study was designed to examine if PKCβII contributes to AGE-induced cardiomyocyte contractile and intracellular Ca(2+) aberrations.
  
  
  METHODS
  Adult rat cardiomyocytes were incubated with methylglyoxal-AGE (MG-AGE) in the absence or presence of the PKCβII inhibitor LY333531 for 12h. Contractile and intracellular Ca(2+) properties were assessed using an IonOptix 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. Oxidative stress, O2(-) production and mitochondrial integrity were examined using TBARS, fluorescence imaging, aconitase activity and Western blotting.
  
  
  RESULTS
  MG-AGE compromised contractile and intracellular Ca(2+) properties including reduced PS, ±dL/dt, prolonged TPS and 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 MG-AGE-induced oxidative stress, O2(-) generation, cell death, apoptosis and mitochondrial injury (reduced aconitase activity, UCP-2 and PGC-1α). In vitro studies revealed that PKCβII inhibition-induced beneficial effects were replicated by the NADPH oxidase inhibitor apocynin and were mitigated by the mitochondrial uncoupler FCCP.
  
  
  CONCLUSIONS
  These findings implicated the therapeutic potential of specific inhibition of PKCβII isoform in the management of AGE accumulation-induced myopathic anomalies.
authors.affiliation: Cardiology Department, The First Affiliated Hospital of PLA General Hospital, Beijing, 100037, China. Electronic address: liweizh304@sina.com.
authors.forename: Liwei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Cardiology Department, The First Affiliated Hospital of PLA General Hospital, Beijing, 100037, China.
authors.forename: Dangsheng
authors.initials: D
authors.lastname: Huang
authors.affiliation: Cardiology Department, The First Affiliated Hospital of PLA General Hospital, Beijing, 100037, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.affiliation: Cardiology Department, The First Affiliated Hospital of PLA General Hospital, Beijing, 100037, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Cardiology Department, The First Affiliated Hospital of PLA General Hospital, Beijing, 100037, China.
authors.forename: Yongjiang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: University of Wyoming College of Health Sciences, Laramie, WY 82071, United States.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Babcock
authors.affiliation: Cardiology Department, The First Affiliated Hospital of PLA General Hospital, Beijing, 100037, China.
authors.forename: Bingyang
authors.initials: B
authors.lastname: Chen
authors.affiliation: University of Wyoming College of Health Sciences, Laramie, WY 82071, United States; Department of Cardiology, Xijing Hospital, Fourth Military Medical University Xi'an, 710032, China. Electronic address: jren@uwyo.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008928:Mitochondria / Q000473:pathology; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors*; D011765:Pyruvaldehyde / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017127:Glycation End Products, Advanced; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011765:Pyruvaldehyde; D064546:Protein Kinase C beta; D000154:Aconitate Hydratase; D002118:Calcium
keywords: Advanced glycation endproduct; Cardiomyocytes; Contractile function; Protein kinase C isoform