Kv1.3 Channel Blockade Improves Inflammatory Profile, Reduces Cardiac Electrical Remodeling, and Prevents Arrhythmia in Type 2 Diabetic Rats

Figures

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  Fig. 1. Metabolic parameters of type 2 diabetic (T2D) rats. a Weekly measurements of fasting plasma glucose. From week 0 to week 6, the diabetic animals were fed with a high-fat (45%) diet. The vertical dotted line indicates the moment of the STZ injection. The horizontal dotted line indicates the upper physiological value of blood glucose. Control animals were fed with standard chow and received an injection of vehicle. b Fasting plasma insulin levels at the end of the experimental period. c IPIGTT at the end of the experimental period. d Area under the curve (A.U.C.) from the data in c. e Evolution of body weight. f Abdominal fat at the end of the experimental period. g, h Plasma circulating levels of cholesterol and triglycerides. Horizontal bars represent Mean ± SEM. One-way ANOVA, followed by the Holm-Bonferroni post hoc test was applied. *p<0.05 with respect to control. #p<0.05 with respect to T2D

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  Fig. 2. T2D-induced cardiac electrical remodeling and increased arrhythmia susceptibility. a Representative ECG recordings at the end of the experimental period. The dashed line shows the end of the T wave. b–d RR interval and main repolarization parameters, QTc, and Tpeak-Tend throughout the 6-week experimental period. Only PAP1 treatment reversed the repolarization abnormalities. One-way ANOVA, followed by the Holm-Bonferroni post hoc test was applied. *p<0.05 with respect to control. #p<0.05 with respect to T2D. e Traces of a non-arrhythmic and an arrhythmic ECG from a control and a T2D animal after caffeine/dobutamine challenge. f Incidence and severity of cardiac arrhythmias in control, T2D animals, and T2D animals treated with metformin or PAP1. No events (NE), ventricular tachycardia (VT), and Torsade de Pointes (TdP)

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  Fig 3. Plasmatic inflammatory profile in T2D. a Plasma levels of IL-1a and IL-13 were not modified in any experimental group. b T2D increased IL-2 and IL-6 levels, which were not modified by any treatment. c T2D increased plasma levels of IL-1b, IL-4, and IL-5, and were normalized by treatment with metformin or PAP1. d T2D increased plasmatic levels of IL-10, IL-12p70, and GM-CSF, which were slightly reduced by metformin and corrected by PAP1. e IFNγ and TNFα were higher in T2D animals, not modified by metformin and corrected by PAP1 treatment. Horizontal bars represent mean ± SEM. One-way ANOVA, followed by the Holm-Bonferroni post hoc test was applied. *p<0.05 with respect to control. #p<0.05 with respect to T2D

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  Fig. 4. Different circulating concentrations of cytokines differentially modulate cardiac repolarization. a Action potentials recorded in ventricular myocytes isolated from healthy animals after 24-h incubation with one of four cocktails of cytokines at the concentrations measured in plasma of Control, T2D, T2D+Met, and T2D+PAP animals. b Incubation with the cytokine cocktail containing IL-10, IL-12p70, GM-CSF, IFNγ, and TNFα, at the concentrations measured in plasma of T2D animals prolonged action potential duration at 90% of repolarization (APD90) and increased action potential triangulation. PAP1 treatment but not metformin partially prevented these repolarization abnormalities. Horizontal bars represent mean ± SEM. n=18, 10, 13, and 11 cells from 7, 7, 4, and 8 animals in control; T2D, T2D+Met, and T2D+PAP respectively. One-way ANOVA, followed by the Holm-Bonferroni post hoc test was applied. *p<0.05 with respect to control. #p<0.05 with respect to T2D