Noncoding RNA in Cardiovascular Disease
Definition
Noncoding RNAs (ncRNAs) are RNA transcripts that are not translated into protein. They comprise >80% of the transcribed human genome and exert diverse regulatory roles in cardiac development, physiology, and disease. Major classes include small ncRNAs (miRNA, snoRNA, Y-RNA, tRNA-derived fragments) and long ncRNAs (lncRNA, circRNA), plus extracellular/circulating forms of all the above. (sources/noncoding-rna-aha-2020 — high)
Key Concepts
MicroRNAs (miRNA)
- 17–22 nt; post-transcriptional repressors via RISC; biogenesis: pri-miRNA → pre-miRNA (Microprocessor) → mature miRNA (Dicer). (sources/noncoding-rna-aha-2020 — high)
- One miRNA can target hundreds of genes (promiscuity); key regulatory nodes in cardiac development, hypertrophy, fibrosis, and arrhythmia
- Therapeutic modulation: anti-miRs, antagomiRs (cholesterol-conjugated), LNA-anti-miRs; catheter-based intracoronary delivery tested; organ-specific delivery remains the main challenge
- Exercise regulation: miR-21, miR-150, miR-222, miR-17-3p upregulated; miR-1, miR-133a, miR-208 downregulated by exercise training
Small Nucleolar RNAs (snoRNA)
- 60–200 nt; nucleolar; guide rRNA/snRNA modifications (C/D box → 2'-O-methylation; H/ACA box → pseudouridylation). (sources/noncoding-rna-aha-2020 — high)
- Rpl13a snoRNAs regulate oxidative stress and are linked to diabetes and doxorubicin cardiotoxicity; Snora73 regulates cholesterol homeostasis via Hummr
- Found in extracellular vesicles; snoRNAs associated with stroke in Framingham Heart Study (SNO1402); snoRNA dysregulation linked to tetralogy of Fallot
Y-RNAs
- 83–112 nt; 4 types in humans; s-RNY fragments (~20–40 nt) measurable in blood. (sources/noncoding-rna-aha-2020 — high)
- Upregulated in macrophages by atherogenic stimuli; elevated in plasma in CAD patients and atherosclerosis mouse models
- EV-YF1 (5'-half of Y-RNA 4 from cardiosphere-derived cell EVs) reduces infarct mass, inflammation, and apoptosis in mouse MI models
- EV-YF1 attenuates cardiac hypertrophy and renal inflammation in angiotensin II mouse model
tRNA-Derived Small RNAs (tsRNA)
- tiRNAs (tRNA halves): generated by angiogenin at anticodon loop; accumulate under stress; upregulated in stroke and hindlimb ischemia models. (sources/noncoding-rna-aha-2020 — high)
- tRFs (tRNA-derived fragments): generated at T/D loops; enriched in isoproterenol-induced hypertrophic hearts; overexpression induces ANP/BNP/α-MHC and cardiomyocyte hypertrophy; target Timp3 (metalloproteinase inhibitor)
- Note: heavy tRNA modifications interfere with sequencing — bacterial AlkB enzyme pre-treatment required
Long Noncoding RNAs (lncRNA)
- See concepts/Long-Noncoding-RNA for detailed treatment
Circular RNAs (circRNA)
- Generated by back-splicing; lack poly(A) tails; resistant to RNase R. (sources/noncoding-rna-aha-2020 — high)
- circANRIL (atheroprotection); circ_lrp4 (smooth muscle cell proliferation/neointima); CDR1as (63× miR-7 binding sites — paradigmatic miRNA sponge)
- Detectable in blood (high stability), but copy numbers low — clinical biomarker utility unproven in large studies
Extracellular RNA (exRNA)
- All ncRNA classes present in circulation, carried in EVs, lipoprotein particles, or RNA-binding proteins. (sources/noncoding-rna-aha-2020 — high)
- FHS exRNA atlas (n=2763) confirms miRNA, piRNA, snoRNA, circRNA, tRNA fragments in human blood
- CVD biomarker associations: AF (miR-21, miR-150), MI (miR-208b, miR-1, miR-133), cardiometabolic disorders
- Major unresolved issue: tissue-specific origin cannot be determined from bulk plasma exRNA; ERCC consortium working to address this
- Quantification highly sensitive to biofluid choice, RNA isolation kit, heparin contamination, and sequencing depth — reproducibility between studies is poor
RNA Therapeutics
- inclisiran (siRNA → PCSK9): N-acetylgalactosamine liver-targeted; sustained LDL-C reduction at 240 days after 2 doses (phase II); phase III ongoing at time of publication. (sources/noncoding-rna-aha-2020 — high)
- patisiran (siRNA → TTR): phase III benefit in ATTR amyloidosis clinical endpoints. (sources/noncoding-rna-aha-2020 — high)
- LNA-anti-miRs/antagomiRs: phase I trials for anti-miR-92a (NCT03603431, NCT03494712) and CDR132L/anti-miR-132 for cardiac remodeling (NCT04045405)
- AAV-miRNA overexpression: AAV-miR-199 in porcine MI model shows efficacy but dose-dependent toxicity — careful dose titration essential
- Main challenges: cardiac-specific delivery, long-term stability, off-target effects, and large RNA (lncRNA) delivery with existing vectors
- See concepts/Gene-Silencing-Therapy for broader context
Contradictions / Open Questions
- ceRNA stoichiometry: Most circRNA/lncRNA-miRNA sponging claims lack rigorous stoichiometric validation; circRNA copy numbers are often far lower than competing miRNA — physiological relevance is frequently overstated. (sources/noncoding-rna-aha-2020 — high)
- exRNA biomarker reproducibility: Multiple high-profile studies report circulating miRNA associations with CVD, but findings are often non-reproducible across different biofluids, RNA isolation methods, and sequencing platforms — no universal normaliser or standardised protocol exists. (sources/noncoding-rna-aha-2020 — high)
- lncRNA micropeptide issue: Up to 20% of lncRNAs in the human heart may encode functional micropeptides — the boundary between noncoding and coding RNA is blurring and classification may need revision. (sources/noncoding-rna-aha-2020 — high)
- tiRNA paradox in ischemia: Angiogenin promotes angiogenesis, but angiogenin-generated tiRNAs inhibit endothelial proliferation, migration, and tube formation — the net physiological effect in ischemic CVD remains unclear. (sources/noncoding-rna-aha-2020 — high)
Connections
- Related to concepts/Long-Noncoding-RNA
- Related to concepts/Gene-Silencing-Therapy
- Related to concepts/AAV-Gene-Delivery
- Related to entities/ATTR-Amyloidosis — patisiran siRNA
- Related to concepts/Lipoprotein-a — inclisiran siRNA