Diabetic cardiomyopathy (DCM) is characterized by diastolic relaxation abnormalities in its initial stages and by clinical heart failure (HF) without dyslipidemia, hypertension, and coronary artery disease in its last stages. DCM contributes to the high mortality and morbidity rates observed in diabetic populations. Diabetes is a polygenic, heritable, and complex condition that is exacerbated by environmental factors. Recent studies have demonstrated that epigenetics directly or indirectly contribute to pathogenesis. While epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs, have been recognized as key players in the pathogenesis of DCM, some of their impacts remain not well understood. Furthering our understanding of the roles played by epigenetics in DCM will provide novel avenues for DCM therapeutics and prevention strategies.
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.
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