title: Chronic effects of mild hyperglycaemia on left ventricle transcriptional profile and structural remodelling in the spontaneously type 2 diabetic Goto-Kakizaki rat.
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 Ca(2+)ATPase, Na(+)/Ca(2+) exchanger and the L-type Ca(2+) channels which may contribute to the altered Ca(2+) 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.
authors: Cardiovascular Research Group, University of Manchester, Manchester, UK.
authors: Alicia
authors: A
authors: D'Souza
authors: Frank C
authors: FC
authors: Howarth
authors: Joseph
authors: J
authors: Yanni
authors: Halina
authors: H
authors: Dobrzynski
authors: Mark R
authors: MR
authors: Boyett
authors: Ernest
authors: E
authors: Adeghate
authors: Keshore R
authors: KR
authors: Bidasee
authors: Jaipaul
authors: J
authors: Singh
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D013997:Time Factors; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling
chemical_list: D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1