Progressive decay of Ca2+ homeostasis in the development of diabetic cardiomyopathy

Shu-Mei Zhao,Chun-Yan Guo,Yong-Liang Wang,Yong-Quan Wu,Jin-Ling Chen

doi:10.1186/1475-2840-13-75

Abstract

BackgroundCardiac dysfunction in diabetic cardiomyopathy may be associated with abnormal Ca2+ homeostasis. This study investigated the effects of alterations in Ca2+ homeostasis and sarcoplasmic reticulum Ca2+-associated proteins on cardiac function in the development of diabetic cardiomyopathy.MethodsSprague–Dawley rats were divided into 4 groups (n = 12, each): a control group, and streptozotocin-induced rat models of diabetes groups, examined after 4, 8, or 12 weeks. Evaluations on cardiac structure and function were performed by echocardiography and hemodynamic examinations, respectively. Cardiomyocytes were isolated and spontaneous Ca2+ spark images were formed by introducing fluorescent dye Fluo-4 and obtained with confocal scanning microscopy. Expressions of Ca2+-associated proteins were assessed by Western blotting.ResultsEchocardiography and hemodynamic measurements revealed that cardiac dysfunction is associated with the progression of diabetes, which also correlated with a gradual but significant decline in Ca2+ spark frequency (in the 4-, 8- and 12-week diabetic groups). However, Ca2+ spark decay time constants increased significantly, relative to the control group. Expressions of ryanodine receptor 2 (RyR2), sarcoplasmic reticulum Ca2+-2ATPase (SERCA) and Na+/Ca2+ exchanger (NCX1) were decreased, together with quantitative alterations in Ca2+regulatory proteins, FKBP12.6 and phospholamban progressively and respectively in the diabetic rats.ConclusionsCa2+ sparks exhibited a time-dependent decay with progression of diabetic cardiomyopathy, which may partly contribute to cardiac dysfunction. This abnormality may be attributable to alterations in the expressions of some Ca2+-associated proteins.

Highlights

Cardiac dysfunction in diabetic cardiomyopathy may be associated with abnormal Ca2+ homeostasis
Heart weights decreased during the 12-week development of diabetes, the difference was statistically significant only in group D compared with the control group (P = 0.013)
With regard to ejection fraction (EF) and fractional shortening (FS), both showed a trend toward gradual decline in the diabetic rats over the 12 weeks, with significant reductions (P < 0.05) appearing at the twelfth week after diabetes was induced (Figure 1)

Summary

Introduction

Cardiac dysfunction in diabetic cardiomyopathy may be associated with abnormal Ca2+ homeostasis. This study investigated the effects of alterations in Ca2+ homeostasis and sarcoplasmic reticulum Ca2+-associated proteins on cardiac function in the development of diabetic cardiomyopathy. Ca2+-induced Ca2+ release plays an important role in the translation of electrical signals to physical contraction in cardiomyocytes, known as excitation-contraction coupling. A small amount of Ca2+ influx through L-type Ca2+ channels can activate a further discharge of Ca2+ from the sarcoplasmic reticulum (SR) via ryanodine receptor 2 (RyR2), resulting in an increase in global intracellular Ca2+ which activates contraction [1]. An imbalance of Ca2+ flux may induce pathological conditions such as arrhythmia and decreased contractility of the cardiomyocytes. It has been reported that a certain portion of the contractile deficit in heart failure is due to an impairment of Ca2+ homeostasis [3,4]

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