Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat

Alicia D'Souza, Frank C. Howarth, Joseph Yanni, Halina Dobryznski, Mark R. Boyett, Ernest Adeghate, Keshore R. Bidasee, Jaipaul Singh

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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.

Original languageEnglish (US)
Pages (from-to)875-888
Number of pages14
JournalExperimental Physiology
Volume96
Issue number9
DOIs
StatePublished - Sep 2011

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Ventricular Remodeling
Prediabetic State
Transforming Growth Factors
Extracellular Matrix
Transcriptome
Heart Ventricles
Diabetic Cardiomyopathies
Connective Tissue Growth Factor
Phenotype
Glucose Intolerance
Brain Natriuretic Peptide
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Fibronectins
Immunoblotting
Cardiac Myocytes
Type 2 Diabetes Mellitus
Hypertrophy
Transcriptional Activation
Blood Glucose

ASJC Scopus subject areas

  • Physiology
  • Nutrition and Dietetics
  • Physiology (medical)

Cite this

D'Souza, A., Howarth, F. C., Yanni, J., Dobryznski, H., Boyett, M. R., Adeghate, E., ... Singh, J. (2011). Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat. Experimental Physiology, 96(9), 875-888. https://doi.org/10.1113/expphysiol.2011.058271

Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat. / D'Souza, Alicia; Howarth, Frank C.; Yanni, Joseph; Dobryznski, Halina; Boyett, Mark R.; Adeghate, Ernest; Bidasee, Keshore R.; Singh, Jaipaul.

In: Experimental Physiology, Vol. 96, No. 9, 09.2011, p. 875-888.

Research output: Contribution to journalArticle

D'Souza, A, Howarth, FC, Yanni, J, Dobryznski, H, Boyett, MR, Adeghate, E, Bidasee, KR & Singh, J 2011, 'Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat', Experimental Physiology, vol. 96, no. 9, pp. 875-888. https://doi.org/10.1113/expphysiol.2011.058271
D'Souza A, Howarth FC, Yanni J, Dobryznski H, Boyett MR, Adeghate E et al. Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat. Experimental Physiology. 2011 Sep;96(9):875-888. https://doi.org/10.1113/expphysiol.2011.058271
D'Souza, Alicia ; Howarth, Frank C. ; Yanni, Joseph ; Dobryznski, Halina ; Boyett, Mark R. ; Adeghate, Ernest ; Bidasee, Keshore R. ; Singh, Jaipaul. / Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat. In: Experimental Physiology. 2011 ; Vol. 96, No. 9. pp. 875-888.
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