Chronic effects of mild hyperglycaemia on left ventricle transcriptional profile and structural remodelling in the spontaneously type 2 diabetic Goto-Kakizaki rat

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Heart failure in chronic type 2 diabetes mellitus is partly attributable to adverse structural remodelling of the left ventricle (LV), but the contribution of hyperglycaemia (HG) per se in remodelling processes is debated. In this study, we examined the molecular signature of LV remodelling in 18-month-old spontaneously diabetic male Goto-Kakizaki (GK) rats that represent a long-term mildly diabetic phenotype, using histological, immunoblotting and quantitative gene expression approaches. Relative to age-matched Wistar controls, mildly diabetic GK rats presented with LV hypertrophy, increased expression of natriuretic peptides and phosphorylation of pro-hypertrophic Akt. Fibrosis proliferation in the GK LV paralleled increased transcriptional and biologically active pro-fibrogenic transforming growth factor-β1 (TGFβ1) in the LV with upregulated mRNA abundance for key extracellular matrix (ECM) components such as fibronectin, collagen type(s) 1 and 3α and regulators including matrix metalloproteinases 2 and 9, and their tissue inhibitor (TIMP) 4, connexin 43 and α5-integrin. GK rats also presented with altered mRNA expression for cardiac sarcoplasmic reticulum Ca2+ ATPase, Na +/Ca2+ exchanger and the L-type Ca2+ channels which may contribute to the altered Ca2+ transient kinetics previously observed in this model at 18 months of age (t test, p < 0.05 vs. age-matched Wistar control for all parameters). The results indicate that chronic mild HG can produce the molecular and structural correlates of a hypertrophic myopathy. Diffuse ECM proliferation in this model is possibly a product of HG-induced TGFβ1 upregulation and altered transcriptional profile of the ECM.

Original languageEnglish (US)
Pages (from-to)65-74
Number of pages10
JournalHeart Failure Reviews
Volume19
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Hyperglycemia
Heart Ventricles
Extracellular Matrix
Ventricular Remodeling
Transforming Growth Factors
Messenger RNA
Natriuretic Peptides
Connexin 43
Collagen Type III
Calcium-Transporting ATPases
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Sarcoplasmic Reticulum
Muscular Diseases
Collagen Type I
Fibronectins
Immunoblotting
Integrins
Type 2 Diabetes Mellitus
Hypertrophy

Keywords

  • Extracellular matrix
  • Goto-Kakizaki rat
  • Transcriptional profile
  • Type 2 diabetes mellitus
  • Ventricular remodelling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Chronic effects of mild hyperglycaemia on left ventricle transcriptional profile and structural remodelling in the spontaneously type 2 diabetic Goto-Kakizaki rat. / D'Souza, Alicia; Howarth, Frank C.; Yanni, Joseph; Dobrzynski, Halina; Boyett, Mark R.; Adeghate, Ernest; Bidasee, Keshore R.; Singh, Jaipaul.

In: Heart Failure Reviews, Vol. 19, No. 1, 01.2014, p. 65-74.

Research output: Contribution to journalArticle

D'Souza, Alicia ; Howarth, Frank C. ; Yanni, Joseph ; Dobrzynski, Halina ; Boyett, Mark R. ; Adeghate, Ernest ; Bidasee, Keshore R. ; Singh, Jaipaul. / Chronic effects of mild hyperglycaemia on left ventricle transcriptional profile and structural remodelling in the spontaneously type 2 diabetic Goto-Kakizaki rat. In: Heart Failure Reviews. 2014 ; Vol. 19, No. 1. pp. 65-74.
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AB - Heart failure in chronic type 2 diabetes mellitus is partly attributable to adverse structural remodelling of the left ventricle (LV), but the contribution of hyperglycaemia (HG) per se in remodelling processes is debated. In this study, we examined the molecular signature of LV remodelling in 18-month-old spontaneously diabetic male Goto-Kakizaki (GK) rats that represent a long-term mildly diabetic phenotype, using histological, immunoblotting and quantitative gene expression approaches. Relative to age-matched Wistar controls, mildly diabetic GK rats presented with LV hypertrophy, increased expression of natriuretic peptides and phosphorylation of pro-hypertrophic Akt. Fibrosis proliferation in the GK LV paralleled increased transcriptional and biologically active pro-fibrogenic transforming growth factor-β1 (TGFβ1) in the LV with upregulated mRNA abundance for key extracellular matrix (ECM) components such as fibronectin, collagen type(s) 1 and 3α and regulators including matrix metalloproteinases 2 and 9, and their tissue inhibitor (TIMP) 4, connexin 43 and α5-integrin. GK rats also presented with altered mRNA expression for cardiac sarcoplasmic reticulum Ca2+ ATPase, Na +/Ca2+ exchanger and the L-type Ca2+ channels which may contribute to the altered Ca2+ transient kinetics previously observed in this model at 18 months of age (t test, p < 0.05 vs. age-matched Wistar control for all parameters). The results indicate that chronic mild HG can produce the molecular and structural correlates of a hypertrophic myopathy. Diffuse ECM proliferation in this model is possibly a product of HG-induced TGFβ1 upregulation and altered transcriptional profile of the ECM.

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