Abstract
Calcium dobesilate (CaD) is used effectively in patients with diabetic microvascular disorder, retinopathy, and nephropathy. Here we sought to determine whether it has an effect on cardiomyocytes calcium mishandling that is characteristic of diabetic cardiomyopathy. Cardiomyocytes were sterile isolated and cultured from 1 to 3 days neonatal rats and treated with vehicle (Control), 25 mM glucose+300 μM Palmitic acid (HG+PA), 100 μM CaD (CaD), or HG+PA+CaD to test the effects on calcium signaling (Ca2+ sparks, transients, and SR loads) and reactive oxygen species (ROS) production by confocal imaging. Compared to Control, HG+PA treatment significantly reduced field stimulation-induced calcium transient amplitudes (2.22 ± 0.19 vs. 3.56 ± 0.21, p < 0.01) and the levels of caffeine-induced calcium transients (3.19 ± 0.14 vs. 3.72 ± 0.15, p < 0.01), however significantly increased spontaneous Ca2+ sparks firing levels in single cardiomyocytes (spontaneous frequency 2.65 ± 0.23 vs. 1.72 ± 0.12, p < 0.01) and ROS production (67.12 ± 4.4 vs. 47.65 ± 2.12, p < 0.05), which suggest that HG+PA treatment increases the Spontaneity Ca2+ spark frequency, and then induced partial reduction of SR Ca2+ content and subsequently weaken systolic Ca2+ transient in cardiomyocyte. Remarkably, these impairments in calcium signaling and ROS production were largely prevented by pre-treatment of the cells with CaD. Therefore, CaD may contribute to a good protective effect on patients with calcium mishandling and contractile dysfunction in cardiomyocytes associated with diabetic cardiomyopathy.
Highlights
The worldwide prevalence of diabetes mellitus increases markedly to cause various cardiovascular complications, which are the major cause of morbidity and mortality in this population [1, 2]
Pre-treatment of cells with Calcium dobesilate (CaD) restored HG+PA–induced alterations in Ca2+ spark frequency, amplitudes, and full width of half maximum (FWHM) (Figures 1A–E). These results suggest that CaD normalizes HG+PA induced RyR dysfunction in the cardiomyocytes at baseline
We found that exposure of neonatal rat ventricular cardiomyocytes to high glucose and high lipid (HG+PA) results in a marked increase in the intracellular reactive oxygen species (ROS) and Ca2+ sparks the frequency, a partial depletion of the sarcoplasmic reticulum (SR) Ca2+ content, and contractile dysfunction
Summary
The worldwide prevalence of diabetes mellitus increases markedly to cause various cardiovascular complications, which are the major cause of morbidity and mortality in this population [1, 2]. Diabetic cardiomyopathy can occur without any vascular pathogenesis [3,4,5]; The disease progress from initial asymptomatic left ventricular (LV) diastolic dysfunction to impaired LV systolic function, and eventually advances to heart failure [6]. Ryanodine receptors play essential role in Ca2+ release from SR via CICR mechanism. Spontaneous Ca2+ sparks, the elementary intracellular Ca2+ release from 4 to 6 neighboring RyRs, is sporadic occurs in the cadiomyocytes under physiological condition. High Spontaneous Ca2+ sparks frequency, often happened in kind of diseases, have been reported to reduce SR Ca2+ content [11]. RyR dysfunction has been shown to cause various of cardiac dysfunction, such as heart failure, hypertrophy [12, 13] and ischemiareperfusion [14]. Abnormal RyR function has been shown in type 1 diabetes [15], and STZ-induced type-2 diabetes rat model [2], despite the pathological significance is not well-characterized
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