Proceedings of The Physiological Society
AstraZeneca (2010) Proc Physiol Soc 18, PC20
Remodelling of the left ventricle in the ageing type 2 diabetic Goto-Kakizaki rat
A. D'Souza1, M. Boyett2, H. Dobrynski2, J. Yanni2, J. Singh1
1. University of Central Lancashire, Preston, United Kingdom. 2. Cardiovascular Medicine, University of Manchester, Manchester, United Kingdom.
Type 2 diabetes mellitus (T2DM) is associated with alterations in cardiac function, partly due to structural remodelling of the left ventricle (LV)1. This study investigates features of LV remodelling in 18 month old spontaneously T2 diabetic Goto Kakizaki (GK) (n=8) rats compared to age-matched Wistar controls (n=8). Blood was collected from the tail vein and blood glucose measured at time zero and 30, 60, 120 and 180 min following intraperitoneal glucose injection (2 g (kg body weight)−1) using previously established methods2. Myocyte size, collagen area fraction, capillary supply and apoptosis in the LV were estimated by histo-morphometric techniques. Quantitative PCR was used to measure the relative expression of mRNA for natriuretic peptides ANP and BNP, collagen type(s) 1& 3α, elastin, fibronectin, matrix-metalloproteinase 2 (MMP2), tissue inhibitor of metalloproteinase(s) 1&4 (TIMP-1, TIMP-4), vimentin, transforming growth factor β1 (TGFβ1), connective tissue growth factor (C-TGF) and calcium handling proteins namely sarcoendoplasmic reticulum Ca2+ATPase, (SERCa2a), sarcolemmal Na+/Ca2+ exchanger (NCX), ryanodine receptor (RyR) and L-type calcium channels (Cav1.2 & Cav1.3). GK rats were moderately hyperglycaemic relative to controls, as verified by fasting blood glucose levels and glucose tolerance testing. Hypertrophy was evident by an increased heart weight to body weight ratio, myocyte diameter and expression of ANP and BNP mRNA (P<0.05, Student's t test). Diabetes produced alterations in sarcomeric structure and reductions in capillary density. Although cardiac pathology frequently manifested as focal scarring, myofibrillar loss, vacuolisation and large clusters of cells showing end-stage apoptosis, caspase-3 activity was unchanged in diabetic vs. control rats (P<0.05, Student's t test). Increased extracellular matrix (ECM) proliferation in the LV of GK rats was concomitant with an augmented expression of mRNA for collagen type(s) 1 & 3α, MMP2, elastin, TIMP-1, TGF-1 and C-TGF(P<0.05, Student's t test). mRNA expression for SERCA2a and the L-type calcium channels were also found to be elevated relative to controls (P<0.05, Student's t test) which may contribute to the altered calcium transient kinetics previously observed in this model2. Results indicate that chronic mild-to-moderate increases in glucose levels appear to accentuate the effects of aging in the LV and elicit a gene expression profile that promotes remodelling of the ECM.
Where applicable, experiments conform with Society ethical requirements