Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice
<p>Structure and expression of NBCe1 major isoforms. (<b>A</b>) An illustration of NBCe1-B protein topology. All NBCe1 isoforms have 14 transmembrane spans (TM1–14), with soluble N-terminal and C-terminal (Nt and Ct) domains located within the cytoplasm. A glycosylated extracellular loop joins TMs 5 and 6. (<b>B</b>) An illustration of sequence differences between NBCe1 isoforms. Due to an alternative upstream promoter that controls NBCe1-B translation, there is a different 85-amino acid (aa) Nt sequence in NBCe1-B (shown in blue) that replaces the first 41 aa residues of NBCe1-A (shown in red). NBCe1-C is identical to NBCe1-B except that the last 46 aa residues of the Ct sequence in NBCe1-B (shown in yellow) are replaced by a different 61 aa sequence (shown in grey) as a consequence of alternative splicing. (<b>C</b>) An illustration of the expression pattern of NBCe1 protein isoforms. The figure was created using BioRender.com.</p> "> Figure 2
<p>Echocardiography demonstrates impaired left ventricular function in KO<sub>b/c</sub> mice. (<b>A</b>) Representative cross-sectional M-mode images of the left ventricle of WT and KO<sub>b/c</sub> mice between 4–5 weeks of age. (<b>B</b>) Heart rates were titrated to between ~400–500 BPM via isoflurane anesthesia. (<b>C</b>) KO<sub>b/c</sub> mice were found to have significantly greater left ventricle internal diameters during diastole (LVIDd) and systole (LVIDs). (<b>D</b>) KO<sub>b/c</sub> mice also had significantly greater end-diastolic volume (EDV) and end-systolic volume (ESV) than WT mice as calculated from LVID measurements. (<b>E</b>) There was no significant difference in stroke volume between WT and KO<sub>b/c</sub> mice. (<b>F</b>) The fractional shortening of KO<sub>b/c</sub> mice was significantly less than that of WT mice. (<b>G</b>) The ejection fraction of KO<sub>b/c</sub> mice was significantly less than that of WT mice. Data presented as mean ± SEM, n = 11–14 per group. Outliers were defined a priori as any point >2 standard deviations from the mean and were excluded from analysis. WT outliers (<span class="html-italic">n</span>) were excluded from LVIDd (1), LVIDs (1), EDV (1), ESV (1), SV (1), FS (1), and EF (2) data sets. KO<sub>b/c</sub> outliers (<span class="html-italic">n</span>) were excluded from heart rate (1), LVIDd (1), LVIDs (1), EDV (1), ESV (1), SV (2), FS (2), and EF (2) data sets. A significant difference between WT and KO<sub>b/c</sub> groups is indicated in the figure by * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, and *** <span class="html-italic">p</span> < 0.001 calculated using Student’s unpaired 2-tailed <span class="html-italic">T</span>-test; ns (non-significant).</p> "> Figure 3
<p>Impaired left ventricular function in KO<sub>b/c</sub> mice is not attributable to differences in left ventricle wall thickness or systemic vascular resistance. During diastole there was no significant difference between the width of the WT and KO<sub>b/c</sub> left ventricle anterior (<b>A</b>) or posterior (<b>B</b>) wall. Similarly, during systole, there was no significant difference between the width of the WT and KO<sub>b/c</sub> left ventricle anterior (<b>C</b>) or posterior (<b>D</b>) wall. (<b>E</b>) There was no significant difference in systolic, diastolic, or mean arterial pressures of awake WT and KO<sub>b/c</sub>. Data presented as mean ± SEM, n = 11–14 per group (panels <b>A</b>–<b>D</b>) or 7–11 per group (panel <b>E</b>). Outliers were defined a priori as any point >2 standard deviations from the mean and were excluded from analysis. WT outliers (<span class="html-italic">n</span>) were excluded from LVAWd (1), LVPWd (1), and LVPWs (1) data sets. KO<sub>b/c</sub> outliers (<span class="html-italic">n</span>) were excluded from LVAWd (1) and LVAWs (1) data sets. Statistical significance calculated using Student’s unpaired 2-tailed <span class="html-italic">T</span>-test; ns (non-significant).</p> "> Figure 4
<p>Left intraventricular pressure–volume (PV) assessment reveals no significant difference between WT and KO<sub>b/c</sub> mice in load-dependent measures of contractility or relaxation. There was no significant difference between WT and KO<sub>b/c</sub> left ventricular end-systolic pressure (<b>A</b>) or end-diastolic pressure (<b>B</b>). There was no significant difference between WT and KO<sub>b/c</sub> mice in their left ventricular maximum rate of pressure change (dP/dt max, representing load-dependent contractility) (<b>C</b>) or in their minimum rate of pressure change (dP/dt min, representing load-dependent relaxation) (<b>D</b>). Heart rates were titrated to between ~300–500 BPM via isoflurane anesthesia (<b>E</b>). Data presented as mean ± SEM, n = 13–14 per group. Outliers were defined a priori as any point >2 standard deviations from the mean and were excluded from analysis. WT outliers (<span class="html-italic">n</span>) were excluded from end-systolic pressure (1), dP/dt max (1), and heart rate (1) data sets. KO<sub>b/c</sub> outliers (<span class="html-italic">n</span>) were excluded from end-systolic pressure (1), end-diastolic pressure (1), dP/dt max (1), dP/dt min (1), and heart rate (1) data sets. A significant difference between WT and KO<sub>b/c</sub> groups is indicated in the figure by *** <span class="html-italic">p</span> < 0.001 calculated using Student’s unpaired 2-tailed <span class="html-italic">T</span>-test; ns (non-significant).</p> "> Figure 5
<p>Left intraventricular pressure–volume (PV) assessment during IVC occlusion reveals diminished load-independent contractility in KO<sub>b/c</sub> mice. Representative PV loops obtained in WT (<b>A</b>) and KO<sub>b/c</sub> (<b>B</b>) mice during IVC occlusion used as a preload reduction maneuver to assess load-independent contractility (slope of the end-systolic pressure volume relationship [ESPVR]) and relaxation (slope of the end-diastolic pressure volume relationship [EDPVR]). (<b>C</b>) The slope of the ESPVR was significantly reduced in KO<sub>b/c</sub> mice. (<b>D</b>) The slope of the EDPVR was not significantly different between WT and KO<sub>b/c</sub> mice. (<b>E</b>) Plotting ESPVR against heart rate for individual mice illustrates that ESPVR is independent of heart rate, supporting that although KO<sub>b/c</sub> mice have a slower heart rate than WT during this experiment, this does not account for the observed reduction in their ESPVR. Data presented as mean ± SEM, n = 12–15 per group. Outliers were defined a priori as any point >2 standard deviations from the mean and were excluded from analysis. A single WT outlier was excluded from the EDPVR data set. A single KO<sub>b/c</sub> outlier was excluded from the ESPVR data set. A significant difference between WT and KO<sub>b/c</sub> groups is indicated in the figure by ** <span class="html-italic">p</span> < 0.01 calculated using Student’s unpaired 2-tailed <span class="html-italic">T</span>-test; ns (non-significant).</p> "> Figure 6
<p>Absence of cardiac hypertrophy in KO<sub>b/c</sub> hearts. (<b>A</b>) Representative low-magnification tiled images, with higher magnified regions of interest (black boxes in low-magnification images), taken of WT and KO<sub>b/c</sub> heart sections stained with H&E. (<b>B</b>) The HW/BW ratio, an index of heart size, was not significantly different between WT and KO<sub>b/c</sub> mice. (<b>C</b>) There was also no significant difference in cross-sectional area between genotypes. Data presented as mean ± SEM, n = 16–18 per group (panel <b>B</b>) or 13–10 per group (panel <b>C</b>). Outliers were defined a priori as any point >2 standard deviations from the mean and were excluded from analysis. A single WT outlier was excluded from the HW/BW ratio data set. A single KO<sub>b/c</sub> outlier was excluded from the HW/BW ratio data set. For panel (<b>B</b>), the statistical significance was calculated using Student’s unpaired 2-tailed <span class="html-italic">T</span>-test. For panel (<b>C</b>), the cross-sectional area of 25–29 cardiomyocytes was measured across 5 images taken around the left ventricle and averaged for each individual mouse, with the statistical significance calculated using hierarchal statistical analysis (nested <span class="html-italic">T</span>-test). ns (non-significant).</p> "> Figure 7
<p>Increased QT length variation in KO<sub>b/c</sub> mice. Representative average ECG cycles of WT (<b>A</b>) and KO<sub>b/c</sub> (<b>B</b>) mice were created from 5 s segments of Lead-I recordings. The black line represents the average trace, with underlying grey lines representing each individual cycle. This method was applied to 30 s Lead-I recordings of WT and KO<sub>b/c</sub> mice from which QT length and QT length variation were assessed. QT length variation was calculated as the coefficient of variation (SD/mean) across 5 s intervals from a continuous 30 s ECG trace (i.e., 6 × 5 s intervals). (<b>C</b>) Heart rates were titrated to between ~350–500 BPM via isoflurane anesthesia. (<b>D</b>) There was no significant difference between the length of the QT interval in WT and KO<sub>b/c</sub> mice. (<b>E</b>) The QT length variation in KO<sub>b/c</sub> was significantly greater than in WT mice. Data presented as mean ± SEM, n = 11–13 per group. A significant difference between WT and KO<sub>b/c</sub> groups is indicated in the figure by *** <span class="html-italic">p</span> < 0.001 calculated using Student’s unpaired 2-tailed <span class="html-italic">T</span>-test; ns (non-significant).</p> "> Figure 8
<p>KO<sub>b/c</sub> cardiomyocytes have reduced Ca<sup>2+</sup>-transient amplitude. (<b>A</b>) Representative Ca<sup>2+</sup> transients recorded in individual cardiomyocytes isolated from WT and KO<sub>b/c</sub> mice loaded with the intracellular Ca<sup>2+</sup> indicator Fura-2 AM. Traces represent the average of ~100 consecutive transients recorded in a single cardiomyocyte while paced at 5 Hz. (<b>B</b>) There was no significant difference between WT and KO<sub>b/c</sub> ‘baseline’ F<sub>340/380</sub> ratio. (<b>C</b>) The ‘peak amplitude’ was significantly decreased in KO<sub>b/c</sub> cardiomyocytes. (<b>D</b>) The ‘peak amplitude as % baseline’ (describing the % change from baseline of the Ca<sup>2+</sup> transient) was also significantly decreased in KO<sub>b/c</sub> cardiomyocytes. (<b>E</b>) There was no significant difference between WT and KO<sub>b/c</sub> in ‘time to peak’. (<b>F</b>) There was no significant difference between WT and KO<sub>b/c</sub> in ‘time to 90% baseline’. (<b>G</b>) There was no significant difference between WT and KO<sub>b/c</sub> the Ca<sup>2+</sup> exponential ‘decay constant (tau)’. Data presented as mean ± SEM, n = 8–9 per group with each point representing the mean of 9–12 cells. Outliers were defined a priori as any point >2 standard deviations from the mean and were excluded from analysis. A single WT outlier was excluded from the ‘time to 90% baseline’ data set. A significant difference between WT and KO<sub>b/c</sub> groups is indicated in the figure by * <span class="html-italic">p</span> < 0.05 calculated using hierarchal statistical analysis (nested <span class="html-italic">T</span>-test); ns (non-significant).</p> ">
Abstract
:1. Introduction
2. Results
2.1. Reduced Ejection Fraction with Diminished Systolic Function in KOb/c Mice
2.2. KOb/c Hearts Are Not Hypertrophic at 4–5 Weeks of Age
2.3. KOb/c Mice Have No Difference in QT Length but Have Increased QT Length Variation
2.4. Cardiomyocytes from KOb/c Mice Have Diminished Ca2+-Transient Amplitude
3. Discussion
4. Materials and Methods
4.1. Mice
4.2. Blood Pressure
4.3. Echocardiography
4.4. Electrocardiogram (ECG) Recording and Analysis
4.5. Intraventricular Admittance Catheter-Derived Pressure–Volume (PV) Analysis
4.6. Histological Analysis
4.7. Cardiomyocyte Isolation
4.8. Ca2+ Transient Recordings and Analysis
4.9. Real-Time PCR
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Brady, C.T.; Marshall, A.; Eagler, L.A.; Pon, T.M.; Duffey, M.E.; Weil, B.R.; Lang, J.K.; Parker, M.D. Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice. Int. J. Mol. Sci. 2024, 25, 9610. https://doi.org/10.3390/ijms25179610
Brady CT, Marshall A, Eagler LA, Pon TM, Duffey ME, Weil BR, Lang JK, Parker MD. Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice. International Journal of Molecular Sciences. 2024; 25(17):9610. https://doi.org/10.3390/ijms25179610
Chicago/Turabian StyleBrady, Clayton T., Aniko Marshall, Lisa A. Eagler, Thomas M. Pon, Michael E. Duffey, Brian R. Weil, Jennifer K. Lang, and Mark D. Parker. 2024. "Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice" International Journal of Molecular Sciences 25, no. 17: 9610. https://doi.org/10.3390/ijms25179610