| First Author | Brady CT | Year | 2024 |
| Journal | Int J Mol Sci | Volume | 25 |
| Issue | 17 | PubMed ID | 39273556 |
| Mgi Jnum | J:360878 | Mgi Id | MGI:7731909 |
| Doi | 10.3390/ijms25179610 | Citation | Brady CT, et al. (2024) Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice. Int J Mol Sci 25(17) |
| abstractText | Congenital proximal renal tubular acidosis (pRTA) is a rare systemic disease caused by mutations in the SLC4A4 gene that encodes the electrogenic sodium bicarbonate cotransporter, NBCe1. The major NBCe1 protein variants are designated NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A expression is kidney-specific, NBCe1-B is broadly expressed and is the only NBCe1 variant expressed in the heart, and NBCe1-C is a splice variant of NBCe1-B that is expressed in the brain. No cardiac manifestations have been reported from patients with pRTA, but studies in adult rats with virally induced reduction in cardiac NBCe1-B expression indicate that NBCe1-B loss leads to cardiac hypertrophy and prolonged QT intervals in rodents. NBCe1-null mice die shortly after weaning, so the consequence of congenital, global NBCe1 loss on the heart is unknown. To circumvent this issue, we characterized the cardiac function of NBCe1-B/C-null (KO(b/c)) mice that survive up to 2 months of age and which, due to the uninterrupted expression of NBCe1-A, do not exhibit the confounding acidemia of the globally null mice. In contrast to the viral knockdown model, cardiac hypertrophy was not present in KO(b/c) mice as assessed by heart-weight-to-body-weight ratios and cardiomyocyte cross-sectional area. However, echocardiographic analysis revealed reduced left ventricular ejection fraction, and intraventricular pressure-volume measurements demonstrated reduced load-independent contractility. We also observed increased QT length variation in KO(b/c) mice. Finally, using the calcium indicator Fura-2 AM, we observed a significant reduction in the amplitude of Ca(2+) transients in paced KO(b/c) cardiomyocytes. These data indicate that congenital, global absence of NBCe1-B/C leads to impaired cardiac contractility and increased QT length variation in juvenile mice. It remains to be determined whether the cardiac phenotype in KO(b/c) mice is influenced by the absence of NBCe1-B/C from neuronal and endocrine tissues. |
