Alternative RNA Splicing in Cardiac Diseases
Alternative RNA Splicing in Cardiac Diseases
Blog Article
Abstract
Alternative RNA splicing is a crucial post-transcriptional mechanism that increases transcript diversity and regulates gene expression. In the heart, precise splicing control is essential for maintaining normal cardiac function. Dysregulation of alternative splicing has been implicated in various cardiac diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmias, and heart failure. This review explores the mechanisms of alternative splicing in cardiac biology, highlights its role in cardiovascular pathologies, and discusses potential therapeutic interventions targeting splicing machinery for cardiac disease treatment.
Introduction
The human genome encodes a limited number of genes, yet alternative RNA splicing significantly expands transcriptomic and proteomic diversity. This process allows a single gene to produce multiple mRNA isoforms with distinct functions, influencing cellular differentiation, metabolism, and stress responses. In the heart, alternative splicing is tightly regulated, contributing to normal development and adaptation to physiological stress. However, splicing dysregulation has been increasingly recognized as a driver of cardiac pathologies.
Mechanisms of Alternative Splicing in the Heart
1. Core Splicing Machinery
Alternative splicing is mediated by the spliceosome, a large ribonucleoprotein complex that recognizes splice sites and assembles mature mRNA transcripts. The process involves:
- Splice donor (5′ splice site) and acceptor (3′ splice site) selection
- Exon inclusion or exclusion
- Use of alternative polyadenylation sites
2. Splicing Regulators in Cardiomyocytes
Splicing factors modulate exon selection and are critical for heart function:
- Serine/arginine-rich (SR) proteins – Promote exon inclusion (e.g., SRSF1, SRSF2).
- Heterogeneous nuclear ribonucleoproteins (hnRNPs) – Often repress splicing (e.g., hnRNP A1, hnRNP H).
- Muscle-specific splicing factors – RBM20 and RBM24 regulate cardiac-specific transcript isoforms.
Role of Alternative Splicing in Cardiac Diseases
1. Dilated Cardiomyopathy (DCM) and Hypertrophic Cardiomyopathy (HCM)
- RBM20 mutations alter splicing of key sarcomeric genes, such as TTN (titin), leading to structural abnormalities in cardiomyocytes.
- Mis-splicing of LDB3 and CAMKIIδ contributes to contractile dysfunction in failing hearts.
2. Arrhythmias and Conduction Disorders
- Alternative splicing regulates ion channels like SCN5A (sodium channels) and CACNA1C (calcium channels), which affect electrical conduction.
- Mis-splicing of KCNH2 and RYR2 can predispose individuals to atrial fibrillation and long QT syndrome.
3. Heart Failure and Cardiac Fibrosis
- BIN1 splicing alterations affect T-tubule organization, disrupting excitation-contraction coupling.
- FHL1 isoforms influence fibroblast activation, contributing to myocardial fibrosis.
Therapeutic Implications of Targeting Alternative Splicing
1. Small Molecule Splicing Modulators
- RNA-targeting therapies (e.g., risdiplam, which enhances exon inclusion) show promise for cardiac disorders.
2. Antisense Oligonucleotides (ASOs)
- ASOs can correct mis-splicing of TTN, RBM20, and SCN5A, restoring normal cardiac protein expression.
3. CRISPR-Based RNA Editing
- Emerging CRISPR-Cas13 technology allows direct RNA modifications, potentially reversing pathogenic splicing events.
Conclusion
Alternative RNA splicing is a key regulatory process in cardiac health and disease. Understanding its role in cardiomyopathies, arrhythmias, and heart failure opens new avenues for RNA-targeted therapies. Future research should focus on identifying splicing biomarkers and developing precise interventions to correct mis-splicing in cardiac diseases.
Keywords
Alternative splicing, RNA processing, cardiomyopathy, arrhythmia, heart failure, RBM20, titin, RNA therapeutics
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