An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities

Figures

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  Figure 1. Representative surface electrocardiogram (ECG) traces recorded in wild-type and neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) C2-knockout mice. Representative ECG traces from wild-type (A) and Nedd4-2 C2-knockout mice (B).

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  Figure 2. Comparison of basal heart rate between wild-type (WT) and Nedd4-2 C2-knockout (KO) mice assessed by radiotelemetry. Male wild-type littermates (n = 4; 14–16 weeks old) and Nedd4-2 C2 −/− mice (n = 5; 14–16 weeks old) were used for this experiment. Telemetered, long-term ECG recordings showed that Nedd4-2 C2 knock-out mice had significantly slower mean heart rates compared with wild-type mice during both the dark and light periods. (A) * p < 0.05, (B) * p < 0.0001. Statistical analyses were performed by repeated measures analysis of variance (ANOVA) followed by Bonferroni multiple comparison tests. * p < 0.0001, ** p = 0.0001 (C).

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  Figure 3. Comparison of basal heart rate variability between wild-type and Nedd4-2 C2-knockout mice assessed by radiotelemetry. Male wild-type littermates (n = 4; 14–16 weeks old) and Nedd4-2 C2 −/− mice (n = 5; 14–16 weeks old) were used for this experiment. VLF, LF and HF components of heart rate variability were significantly higher in Nedd4-2 C2 knock out (KO) knockout mice than wild-type mice (A). The coefficient between LF and HF spectral power density, which is presumed to reflect sympatho-vagal balance, was significantly increased in Nedd4-2 C2 KO mice (B). VLF; Very low frequency, HF; High-frequency, LF; Low frequency. * p < 0.0001.

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  Figure 4. Representative hearts from sham-operated and left anterior descending artery ligated mice. Whole hearts (A) and microscopic findings (B) of the infarcted regions are shown (arrows). Sections stained with Masson’s trichrome stain (B) are shown by ×100 magnification under light microscopic examination using a BZ-9000 fluorescence microscope (Keyence, Osaka, Japan). The ruler shows millimeter markings. WT: wild-type, KO: knockout, MI: myocardial infarction.

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  Figure 5. Comparison of electrocardiographic findings between wild-type and Nedd4-2 C2-knockout mice after myocardial infarction. Male wild-type littermates (n = 4; 11–14 weeks old) and Nedd4-2 C2 −/− mice (n = 4; 11–14 weeks old) were used for this experiment. A for PR intervals, B for QRS intervals, C for QTc intervals, and D for T peak T end intervals, respectively. Data are expressed as means ± SE. Nedd4-2 C2-knockout mice showed enhancement of T peak/T end interval with surgical ligation of the distal left coronary artery. MI; myocardial infarction. * p < 0.0001, ** p < 0.001.

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  Figure 6. Increased daily urinary catecholamine excretion in Nedd4L C2-knockout (KO) mice. Daily urinary (A) catecholamine, (B) noradrenaline, and (C) dopamine excretion in wild-type (WT) and Nedd4L C2 KO mice. Male wild-type littermates (n = 4; 8–9 weeks old) and Nedd4-2 C2 −/− mice (n = 8; 8 weeks old) were used for this experiment. Data are expressed as means ± SE. Statistical analyses were performed by unpaired, two-tailed Student t test. * p = 0.0191, ** p = 0.0329, NS; not significant.