Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC143
Impact of age on structural remodelling in the spontaneously diabetic Goto Kakizaki rat
A. D'Souza1, F. C. Howarth2, E. Adeghate2, K. R. Bidasee3, J. Singh1
1. Schools of Pharmacy and Forensic and Investigative Sciences, University of Central Lancashire, Preston, United Kingdom. 2. Departments of Physiology and Anatomy, UAE University, Al Ain, United Arab Emirates. 3. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Centre, Omaha, Nebraska, United States.
The cardiac effects of type 2 diabetes mellitus (T2DM) are known to be most pronounced in the elderly.Chronic hyperglycaemia (HG) may underlie this process by producing structural changes that alter left ventricle (LV) function. However, the mechanisms via which HG affects the heart specifically to accelerate the effects proper to ageing are relatively unknown. This study investigated the effect of ageing on dysglycaemia-related myocardial remodelling and associated molecular events in the spontaneously diabetic Goto Kakizaki (GK) rat. Mildly diabetic GK rats 2 months (young) and 18 months (old) of age and age-matched Wistar controls were humanely killed in accordance with Institutional Regulations after administration of an oral glucose tolerance test and measurement of blood glucose collected from the tail vein to confirm HG. LV samples were collected for histological, immunohistochemical and gene expression analyses using methods described elsewhere . The results (mean±SEM) showed that interstitial fibrosis area fraction (1.44±1.02% in young and 7.38±0.50% in old GK rats vs. 1.006±0.13% and 5.87±0.54% in respective age-matched controls, Student’s t-test; p<0.05), mean heart weight/body weight ratio (0.32±0.59 ratio units in young and 1.41±0.16 ratio units in old GK rats vs. 0.23±4.48 and 1.22±0.2 ratio units in respective controls, p<0.05), LV wall thickness (3.15±0.46 mm in young and 3.35±0.17 mm in old GK rats vs. 2.98 ±2.07 and 3.08±2.39 mm in respective age-matched controls, p<0.05) and myocyte diameter (9.93±2.69 µm in young and 11.34±0.54 µm in old G-K rats vs. 9.11±2.55 and 9.43±0.35 µm in respective age-matched controls, p<0.05) demonstrated a trend towards greater fibrosis proliferation and LV hypertrophy with ageing. The effect was also accentuated by the presence of T2DM in the GK rats (2-way ANOVA, p<0.05). These alterations were concomitant with up-regulated active pro-fibrotic Transforming growth factor beta 1 (TGFβ1) activity (2.89±0.60 vs. 5.47±1.48 pg/mg (total protein) in young control and GK rats and 2.12±0.54 vs. 5.4±0.74 pg/mg (total protein) in old control and GK LV, p<0,05) and gene expression in the diabetic groups relative to control. (1.15±3.32 vs. 1.76±22 ratio units normalised to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in young control vs. GK rats and 0.97±0.14 vs 1.92±0.17 ratio units normalised to GAPDH in old control vs G-K rats, p<0.01). Finally, levels of phosphorylation of pro-hypertrophic Akt and p70S6K were also significantly up-regulated in dysglycaemic groups ( p<0.05), but age related effects were not apparent (2-way ANOVA, p>0.05). The results of this study have demonstrated that chronic moderate elevations in HG can aggravate age-induced remodelling changes in the GK myocardium. In addition, elevated levels of TGFβ1 and altered Akt signalling may be key intermediaries in this process.
Where applicable, experiments conform with Society ethical requirements