Pathologic cardiac messenger RNA (mRNA)

Pathologic cardiac messenger RNA (mRNA) refers to the set of protein-coding transcripts that are abnormally regulated during the progression of heart diseases such as heart failure, myocardial infarction, and hypertrophy. A hallmark of cardiac pathology is the reactivation of the "fetal gene program," where the heart shifts its transcriptional profile to favor embryonic isoforms, such as the transition from alpha-myosin heavy chain (MYH6) to beta-myosin heavy chain (MYH7) (Source: Circulation Research, doi:10.1161/CIRCRESAHA.113.300210). These mRNA changes are not merely markers of disease but are active drivers of maladaptive remodeling, fibrosis, and contractile dysfunction (Source: Nature Reviews Cardiology, doi:10.1038/s41569-020-0392-8). Therapeutic targeting of these mRNAs involves the use of RNA-based modalities, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), which are designed to selectively reduce the levels of harmful transcripts or correct aberrant splicing (Source: JACC: Basic to Translational Science, doi:10.1016/j.jacbts.2021.01.010). Additionally, small molecule epigenetic modulators like HDAC inhibitors can influence the overall landscape of pathologic mRNA expression (Source: Journal of Clinical Investigation, doi:10.1172/JCI64535). While these approaches offer high specificity, significant challenges remain regarding the efficient delivery of these large, negatively charged molecules to cardiomyocytes and the mitigation of potential off-target effects in the liver or immune system (Source: Molecular Therapy, doi:10.1016/j.ymthe.2018.12.011). Future developments in cardiac-targeted delivery systems, such as lipid nanoparticles or viral vectors, are essential for the clinical success of mRNA-targeted therapies.

Other names

Fetal gene program transcriptsCardiac disease-associated mRNAMaladaptive cardiac transcriptome

Targeted degradation of mRNA via RNase H recruitment or the RNA-induced silencing complex (RISC), and modulation of pre-mRNA splicing to prevent the production of pathologic protein isoforms (Source: Nature Reviews Drug Discovery, doi:10.1038/nrd.2017.153).