Abstract 4368896: The link between distinct serum response factor isoforms and cardiovascular disease: diagnostic and therapeutic potential?

Abstract

Background: Serum Response Factor (SRF) is an important transcription factor for cardiac muscle gene regulation. Alternative splicing of SRF may modulate different cardiac disease. This study investigates SRF-related alternative splicing events (ASEs) across cardiomyopathy using patient’s RNA-Seq datasets. Hypothesis: We hypothesize that SRF may undergo disease-specific alternative splicing in cardiomyopathies, and resulting spliced isoforms modulate disease progression through altered transcriptional regulation of cardiac genes. Methods: To evaluate SRF-associated splicing events in a variety of patient categories, such as non-ischemic cardiomyopathy (NICM), ischemic cardiomyopathy (ICM), patients with left ventricular assist devices (LVAD), dilated cardiomyopathy (DCM), Heart failure with reduced ejection fraction (HFrEF) and Non failure (NF), RNA-Seq datasets PRJNA198165, PRJNA477855, and PRJNA487360 were examined. Skipped exons (SE), alternative 5' splice sites (A5SS), alternative 3' splice sites (A3SS), mutually exclusive exons (MXE), and retained introns (RI) were the conventional classifications for ASEs. UpSet plot and Heatmap depicted event overlaps and relative splicing patterns in different cardiac diseases. Results: In dataset PRJNA198165, comprising patient groups: NICM+NF, NICM LVAD+NF, ICM+NF, and ICM LVAD+NF, SE events were the most common form of ASEs in all groups. The ICM LVAD + NF group had a slightly greater total number of splicing events (17 events) than the other groups (16 events each). This suggests that mechanical unloading via LVAD may enhance splicing variability of SRF, especially in ischemic cardiomyopathy. In the PRJNA678360 dataset which include samples from left and right atria and ventricles, 24 ASEs were identified per group. SE (n = 52) and MXE (n = 14) were common, indicating a conserved splicing response across HFrEF. In PRJNA477855, comparing ICM+NF and (DCM +NF), four splicing events were identified in each group, SE events were the most prevalent (n = 6), followed by A5SS events (n = 2). No events were detected in the A3SS, MXE, or RI categories. These findings indicate SE events may play a central role in the transcriptomic differences between cardiomyopathy subtypes. Conclusion: These finding reports that SRF undergoes consistent and condition-specific splicing alteration in cardiovascular disease. The predominance of SE events suggests their potential as mechanistic markers or therapeutic targets.