title: The Impact of Chronic Glycogen Synthase Kinase-3 Inhibition on Remodeling of Normal and Pre-Diabetic Rat Hearts.
abstract: OBJECTIVE
  There is an ongoing search for new drugs and drug targets to treat diseases like Alzheimer's disease, cancer and type 2 diabetes (T2D). Both obesity and T2D are characterized by the development of a cardiomyopathy associated with increased hypertension and compensatory left ventricular hypertrophy. Small, specific glycogen synthase kinase-3 (GSK-3) inhibitors were developed to replace lithium chloride for use in psychiatric disorders. In addition, they were advocated as treatment for T2D since GSK-3 inhibition improves blood glucose handling. However, GSK-3 is a regulator of hypertrophic signalling in the heart via phosphorylation of NFATc3 and β-catenin respectively. In view of this, we hypothesized that chronic inhibition of GSK-3 will induce myocardial hypertrophy or exacerbate existing hypertrophy.
  
  
  METHODS
  Rats with obesity-induced prediabetes were treated orally with GSK-3 inhibitor (CHIR118637 (CT20026)), 30 mg/kg/day for the last 8 weeks of a 20-week diet high in sugar content vs a control diet. Biometric and biochemical parameters were measured, echocardiography performed and localization and co-localization of NFATc3 and GATA4 determined in cardiomyocytes.
  
  
  RESULTS
  Obesity initiated myocardial hypertrophy, evidenced by increased ventricular mass (1.158 ± 0.029 vs 0.983 ± 0.03 g) and enlarged cardiomyocytes (18.86 ± 2.25 vs 14.92 ± 0.50um(2)) in association with increased end-diastolic diameter (EDD = 8.48 ± 0.11 vs 8.15 ± 0.10 mm). GSK-3 inhibition (i) increased ventricular mass only in controls (1.075 ± 0.022 g) and (ii) EDD in both groups (controls: 8.63 ± 0.07; obese: 8.72 ± 0.15 mm) (iii) localized NFATc3 and GATA4 peri-nuclearly.
  
  
  CONCLUSIONS
  Indications of onset of myocardial hypertrophy in both control and obese rats treated with a GSK-3 inhibitor were found. It remains speculation whether these changes were adaptive or maladaptive.
authors.affiliation: Department of Biomedical Sciences, Division of Medical Physiology, Faculty of Medicine and Health Sciences, University of Stellenbosch, P.O. Box 19063, Tygerberg, 7505, Republic of South Africa. bh3@sun.ac.za.|South African Medical Research Council Biomedical Research and Innovation Platform, Tygerberg, 7505, South Africa. bh3@sun.ac.za.
authors.forename: B
authors.initials: B
authors.lastname: Huisamen
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway.
authors.forename: T Lubelwana
authors.initials: TL
authors.lastname: Hafver
authors.affiliation: Imaging Unit - Central analytical Facility, University of Stellenbosch, Stellenbosch, 7600, South Africa.
authors.forename: D
authors.initials: D
authors.lastname: Lumkwana
authors.affiliation: Department of Biomedical Sciences, Division of Medical Physiology, Faculty of Medicine and Health Sciences, University of Stellenbosch, P.O. Box 19063, Tygerberg, 7505, Republic of South Africa.
authors.forename: A
authors.initials: A
authors.lastname: Lochner
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000209:etiology* / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D003920:Diabetes Mellitus / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000000981:diagnostic imaging / Q000209:etiology* / Q000378:metabolism; D004452:Echocardiography; D050991:GATA4 Transcription Factor / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006321:Heart / Q000000981:diagnostic imaging; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D050991:GATA4 Transcription Factor; C084365:Gata4 protein, rat; D007004:Hypoglycemic Agents; D007328:Insulin; D050778:NFATC Transcription Factors; C445503:transcription factor NF-AT c3; D038362:Glycogen Synthase Kinase 3
keywords: Cardiac hypertrophy; GATA4; GSK-3; NFATc3; Pre-diabetes