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Heart Failure Reviews

, Volume 19, Issue 1, pp 65–74 | Cite as

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
Article

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.

Keywords

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

Notes

Conflict of interest

None.

Supplementary material

10741_2013_9376_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 17 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Alicia D’Souza
    • 1
  • Frank C. Howarth
    • 2
  • Joseph Yanni
    • 1
  • Halina Dobrzynski
    • 1
  • Mark R. Boyett
    • 1
  • Ernest Adeghate
    • 2
  • Keshore R. Bidasee
    • 3
  • Jaipaul Singh
    • 4
  1. 1.Cardiovascular Research GroupUniversity of ManchesterManchesterUK
  2. 2.Faculty of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUAE
  3. 3.Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CentreOmahaUSA
  4. 4.School of Forensic and Investigative ScienceUniversity of Central LancashirePrestonUK

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