title: Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat.
abstract: This study tested the hypothesis that experimental prediabetes can elicit structural remodelling in the left ventricle (LV). Left ventricles isolated from 8-week-old male Goto-Kakizaki (GK) rats and age-matched male Wistar control rats were used to assess remodelling changes and underlying transforming growth factor β1 (TGFβ1) activity, prohypertrophic Akt-p70S6K1 signalling and gene expression profile of the extracellular matrix (ECM) using histological, immunohistochemical, immunoblotting and quantitative gene expression analyses. Prediabetes in GK rats was confirmed by impaired glucose tolerance and modestly elevated fasting blood glucose. Left ventricle remodelling in the GK rat presented with marked hypertrophy of cardiomyocytes and increased ECM deposition that together translated into increased heart size in the absence of ultrastructural changes or fibre disarray. Molecular derangements underlying this phenotype included recapitulation of the fetal gene phenotype markers B-type natriuretic peptide and α-skeletal muscle actin, activation of the Akt-p70S6K1 pathway and altered gene expression profile of key components (collagen 1α and fibronectin) and modulators of the ECM (matrix metalloproteinases 2 and 9 and connective tissue growth factor). These changes were correlated with parallel findings of increased TGFβ1 transcription and activation in the LV and elevated active TGFβ1 in plasma of GK rats compared with control animals (Student's t test, P < 0.05 versus age-matched Wistar control animals for all parameters). This is the first report to describe LV structural remodelling in experimental prediabetes. The results suggest that ventricular decompensation pathognomonic of advanced diabetic cardiomyopathy may have possible origins in profibrotic and prohypertrophic mechanisms triggered before the onset of type 2 diabetes mellitus.
authors.affiliation: School of Forensic and Investigative Science, University of Central Lancashire, Preston, Lancashire PR1 2HE, UK.
authors.forename: Alicia
authors.initials: A
authors.lastname: D'Souza
authors.forename: Frank C
authors.initials: FC
authors.lastname: Howarth
authors.forename: Joseph
authors.initials: J
authors.lastname: Yanni
authors.forename: Halina
authors.initials: H
authors.lastname: Dobryznski
authors.forename: Mark R
authors.initials: MR
authors.lastname: Boyett
authors.forename: Ernest
authors.initials: E
authors.lastname: Adeghate
authors.forename: Keshore R
authors.initials: KR
authors.lastname: Bidasee
authors.forename: Jaipaul
authors.initials: J
authors.lastname: Singh
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D008297:Male; D020097:Natriuretic Peptide, Brain; D011236:Prediabetic State / Q000503:physiopathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D020257:Ventricular Remodeling
chemical_list: D016326:Extracellular Matrix Proteins; D053773:Transforming Growth Factor beta1; D020097:Natriuretic Peptide, Brain; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1