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Cellular mechanisms of STZ-induced diabetic cardiomyopathy

M-L. Ward,1 L. Zhang,1,2 A.R.J. Phillips2,4,5 and G.J.S. Cooper,2,3,5 1Department of Physiology, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1023, New Zealand., 2School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1023, New Zealand., 3Department of Medicine, FMHS, University of Auckland, Private Bag 92019, Auckland 1023, New Zealand., 4Department of Surgery, FMHS, University of Auckland, Private Bag 92019, Auckland 1023, New Zealand. and 5Protemix Corporation, Auckland, New Zealand..

Sustained diabetes mellitus leads to a deterioration of heart function, which occurs independently of the macro- and micro-vascular diseases. In humans, development of diabetic cardiomyopathy is associated with increased risk of heart failure, but our understanding of the cellular mechanisms underlying diabetic cardiomyopathy remain unclear. Myocardial Ca2+ homeostasis has been reported to be altered during diabetes, and is believed to be involved in the diabetes-induced primary cardiomyopathy (Dhalla et al., 1982). As well, extracellular matrix changes have also been implicated (Cooper et al., 2004). The aim of this study was to investigate Ca2+ homeostasis, myocardial contractility, and extracellular matrix remodeling in an animal model of diabetes, in order to gain insights into the mechanisms underlying diabetic heart disease.

ECG measurements from anaesthetized animals (halothane, flow rate 2 ml/min with 100% O2) immediately prior to euthanasia and dissection of trabeculae showed that the normalized QT interval was prolonged in diabetic rats (STZ: 0.192 ± 0.004 s, (n = 18); Control: 0.177 ± 0.004 s, (n = 11)), as was action potential duration (AP90) recorded from the LV free-wall of isolated, perfused, hearts (STZ: 0.195 ± 0.009 s (n = 7); Control: 0.136 ± 0.010 s (n = 6)). Simultaneous measurements were made of isometric force and intracellular calcium ([Ca2+]i, as the ratio of fura-2/AM fluorescence), in left-ventricular trabeculae from STZ, and their age-matched Controls under physiological conditions (37 °C, 5 Hz and pH 7.4). STZ-induced diabetic rats, 8 weeks post injection, had depressed cardiac contractility. Peak systolic stress was decreased in STZ (STZ: 10 ± 1 mN mm-2; Control: 17 ± 2 mN mm-2, n = 7 in each group), with slower time to peak stress (STZ: 77 ± 3 ms; Control: 67 ± 7 ms) and time to 90% relaxation of stress (STZ: 76 ± 7 ms; Control: 56 ± 3 ms). Histological studies of fixed LV free wall showed that the structure of the thin myofilament (f-actin) was disrupted in diabetic hearts, and the content reduced. Despite the obvious contractile dysfunction, no discernable difference was found in the amplitude of the Ca2+ transient in diabetic rats, although the time constant of Ca2+ transient decay was slower (STZ: 61 ± 3 ms; Control: 49 ± 3 ms). Western blot analysis of SERCA2a and Na+/Ca2+ exchanger expression was carried out in LV tissue from 8 week post-injection animals. It was found that SERCA2a expression was reduced in diabetic hearts, without significant changes of Na+/Ca2+ exchanger expression. SERCA2a is the major Ca2+ transport protein responsible for rapid removal of cytosolic Ca2+, thereby allowing relaxation to occur.

In conclusion, both prolonged action potential duration, and decreased expression of SERCA2a can explain the slower kinetics of the Ca2+ transient in diabetic rats, whereas the reduced contractility is more likely to be associated with the changes in f-actin content and structure.

Dhalla, NS, Pierce GN, Panagia V, Singal PK, & Beamish RE. (1982) Basic Research in Cardiology, 77: 117-139.

Cooper GJ, Phillips AR, Choong SY, Leonard BL, Crossman DJ, Brunton DH, Saafi L, Dissanayake AM, Cowan BR, Young AA, Occleshaw CJ, Chan YK, Leahy FE, Keogh GF, Gamble GD, Allen GR, Pope AJ, Boyd PD, Poppitt SD, Borg TK, Doughty RN & Baker JR. (2004) Diabetes 53: 2501-2508.

This study was approved by the University of Auckland Animal Ethics Committee, and supported by Health Research Council of New Zealand, and Protemix Corporation.