Exploring m6A RNA modification as a therapeutic target in cardiovascular disorders

Emerging research highlights the transformative potential of m6A RNA modification in the diagnosis and treatment of cardiovascular diseases (CVDs). As the most abundant internal modification of eukaryotic RNA, m6A is pivotal in regulating gene expression, RNA metabolism, and cellular processes. Understanding its role in CVDs could revolutionize therapeutic strategies, offering new pathways to manage conditions like coronary artery disease (CAD), heart failure (HF), pulmonary hypertension (PH), and arrhythmias (AH).

The mechanism of m6A modification involves the dynamic interaction between methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). These molecular players regulate the addition and removal of m6A marks on RNA, influencing processes such as mRNA stability, translation efficiency, and gene transcription. In the context of cardiovascular health, dysregulation of m6A has been linked to vascular inflammation, endothelial dysfunction, and cardiac remodeling.

One of the most promising aspects of m6A research lies in its role in coronary artery disease. Elevated m6A levels have been associated with chronic inflammation, atherosclerotic plaque formation, and vascular smooth muscle cell proliferation. m6A-modifying enzymes like METTL3 and METTL14 influence the expression of genes involved in lipid metabolism and vascular integrity, potentially offering new targets for atherosclerosis treatment. Additionally, FTO-mediated demethylation of m6A-modified RNA has been linked to the regulation of adipogenesis, highlighting its relevance in managing metabolic risk factors associated with CAD.

In the case of heart failure, m6A modification affects myocardial cell apoptosis, calcium homeostasis, and ventricular remodeling. Upregulated m6A levels can impair cardiomyocyte function and exacerbate ventricular hypertrophy. Conversely, downregulation of m6A methyltransferases may enhance cardiac repair mechanisms, offering potential for regenerative therapies. The interaction between m6A and cardiac-specific RNAs like MHRT and SERCA2a underscores its influence on contractile function and cardiac remodeling.

Pulmonary hypertension also demonstrates a significant relationship with m6A, particularly in regulating smooth muscle cell proliferation and vascular remodeling. Modulating m6A marks on key transcripts like FOXO1 and MAGE-D1 may reduce pulmonary artery pressure and improve vascular resistance, presenting a potential strategy for PH management.

In the realm of arrhythmias, m6A regulation of calcium signaling pathways and autonomic nerve activity can affect cardiac electrical stability. Dysregulated m6A modifications have been observed in conditions like atrial fibrillation, where they impact ion channel expression and sympathetic hyperactivity. Targeting m6A-related pathways could help stabilize cardiac rhythm and reduce arrhythmic risk.