MicroRNA-135a regulation of sodium calcium exchanger gene expression in cardiomyocytes
Bibliographic record
Abstract
MicroRNAs (miRNAs) are key regulators of cardiac electrical and structural remodeling and are implicated in pathologies such as arrhythmias, ischemic heart disease and hypertrophy. miRNA expression has yet to be studied in the context of complete atrioventricular block (CAVB) and the subsequent bradycardic arrhythmogenic remodeling. A time course microarray and RT-qPCR analysis of left ventricular miRNA expression in a mouse CAVB model revealed a strong, early and sustained reduction in miR-135a over 4 weeks, a miRNA unexplored in the cardiovascular field. Several other miRNAs were differentially expressed by 4 weeks post-CAVB as well.To better understand the role of miR-135a in the cardiomyocyte, we identified relevant target genes using literature searches and prediction algorithms, followed by biological confirmation using miR-135a overexpression with luciferase assays, real time qPCR and Western blot. Na+-Ca2+ exchanger 1 (NCX1), encoded by the gene SLC8A1, was identified as a regulated gene; miR-135a overexpression reduced NCX1 3'UTR luciferase reporter activity (-42%) and NCX1 mRNA (-47%) and protein (-35%) expression. Given the significance of NCX1 activity in automaticity and Ca2+ handling in neonatal cardiomyocytes, we sought to investigate the functional effects of miR-135a overexpression in spontaneously beating primary neonatal rat ventricular myocytes (NRVMs). 72-hour overexpression of miR-135a reduced spontaneous beating frequency at 33oC from 147±8 bpm (negative control) to 55±6 bpm, and caused beat-to-beat interval irregularities. Ca2+ transient measurements (fura-2 AM) demonstrated no miR-135a associated alterations when NRVMs were electrically stimulated at 2 Hz; however, rapid application of 20-mM caffeine revealed an increase in decay time constant (+54%) in miR-135a NRVMs. Additionally, the Ca2+ overloading toxic effects of 100-µM ouabain, a cardiac glycoside reliant on NCX1 activity, was eliminated by miR-135a overexpression, further reducing potentially arrhythmogenic spontaneous Ca2+ release events (SCREs). The findings of this study illustrate that miR-135a overexpression negatively regulates NCX1 expression, leading to alterations of NRVM automaticity, Ca2+ extrusion rate, arrhythmogenic Ca2+ loading and SCREs. miR-135a may contribute to pro-arrhythmic remodeling following CAVB.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".