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

Abstract

Objective: This study examines the extent to which the contractile deficit of diabetic cardiomyopathy is due to altered Ca²⁺ homeostasis.

Methods: Measurements of isometric force and intracellular calcium ([Ca²⁺]_i,fura-2/AM) were made in left ventricular trabeculae from streptozotocin (STZ)-induced diabetic rats and age-matched siblings.

Results: At 1.5 mmol/L [Ca²⁺]_o, 37 °C, and 5 Hz stimulation frequency, peak stress was depressed in diabetic rats (10 ±1 mN/mm² vs 17 ±2 mN/mm² control, P<0.05) with a slower time-to-peak stress (77 ±03ms vs. 67 ±2ms control, P<0.01) and time-to-90% relaxation (76 ±7ms vs; 56 ±3ms control, P<0.05). No difference was found between groups for either resting or peak Ca²⁺, but the Ca²⁺ transient was slower in time-to-peak (39 ±2ms vs. 34 ±1ms control) and decayed more slowly (time constant, 61 ±3ms vs 49 ±3ms control). Diabetic rats had a longer LV action potential (APD₅₀, 98 ±5ms vs. 62 ±5ms control, P<0.0001). Western blotting showed that diabetic rats had a reduced expression of SERCA2a, with no difference in expression of the Na⁺/Ca²⁺-exchanger. Immunohistochemistry of LV free wall showed 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.

Conclusions: We find no evidence to support the idea that altered Ca²⁺ homeostasis underlies the contractile deficit of diabetic cardiomyopathy. The slower action potential and reduced SERCA2a expression can explain the slower Ca²⁺ transient kinetics in diabetic rats, but not the contractile deficit. Instead, we suggest that the observed LV remodeling may play a crucial role.