Altered calcium homeostasis does not explain the contractile deficit of diabetic cardiomyopathy.

Abstract

This study examines the extent to which the contractile deficit of diabetic cardiomyopathy is due to altered Ca(2+) homeostasis. Measurements of isometric force and intracellular calcium ([Ca(2+)](i), using fura-2/AM) were made in left ventricular (LV) trabeculae from rats with streptozotocin-induced diabetes and age-matched siblings. At 1.5 mmol/l [Ca(2+)](o), 37 degrees C, and 5-Hz stimulation frequency, peak stress was depressed in diabetic rats (10 +/- 1 vs. 17 +/- 2 mN/mm(2) in controls; P < 0.05) with a slower time to peak stress (77 +/- 3 vs. 67 +/- 2 ms; P < 0.01) and time to 90% relaxation (76 +/- 7 vs. 56 +/- 3 ms; P < 0.05). No difference was found between groups for either resting or peak Ca(2+), but the Ca(2+) transient was slower in time to peak (39 +/- 2 vs. 34 +/- 1 ms) and decay (time constant, 61 +/- 3 vs. 49 +/- 3 ms). Diabetic rats had a longer LV action potential (APD(50), 98 +/- 5 vs. 62 +/- 5 ms; P < 0.0001). Western blotting showed that diabetic rats had a reduced expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a, with no difference in expression of the Na(+)/Ca(2+) exchanger. Immunohistochemistry of LV free wall showed that type I collagen was increased in diabetic rats (diabetic 7.1 +/- 0.1%, control 12.7 +/- 0.1%; P < 0.01), and F-actin content reduced (diabetic 56.9 +/- 0.6%; control 61.7 +/- 0.4%; P < 0.0001) with a disrupted structure. We find no evidence to support the idea that altered Ca(2+) homeostasis underlies the contractile deficit of diabetic cardiomyopathy. The slower action potential and reduced SERCA2a expression can explain the slower Ca(2+) transient kinetics in diabetic rats but not the contractile deficit. Instead, we suggest that the observed LV remodeling may play a crucial role.