Impact of RNA Splicing on Endothelial Function in CVD
Protein changes resulting from aberrant RNA splicing in endothelial cells are not merely bystanders but are increasingly recognized as active drivers of cardiovascular disease (CVD).
To answer your question directly: these changes contribute to CVD to a significant extent by creating "molecular switches" that can flip a healthy endothelial cell into a diseased state without necessarily changing the total amount of the gene being expressed. This process often explains why a patient might have "normal" levels of a protein but impaired function.
The following sections analyze the extent of this impact, categorizing how splicing changes cause endothelial problems that lead to specific cardiovascular pathologies.
1. The "Dominant-Negative" Effect (Loss of Protection)
One of the most damaging ways splicing changes cause disease is by producing "decoy" or "broken" proteins that actively sabotage healthy ones. This is a major cause of endothelial dysfunction.
The Protein: eNOS (Endothelial Nitric Oxide Synthase)
- Normal Function: Produces Nitric Oxide (NO) to relax vessels and prevent clotting.
- Splicing Error: A truncated splice variant (e.g., eNOS13A) is produced.
- Endothelial Problem: This variant acts as a "dominant negative," essentially turning off the healthy protein.
- CVD Outcome: Reduced NO bioavailability causes hypertension and accelerates atherosclerosis.
The Protein: VEGF Receptor (Flt-1)
- Normal Function: Receives growth signals (VEGF) to keep endothelium healthy.
- Splicing Error: The cell switches to producing a soluble form called sFlt-1.
- Endothelial Problem: sFlt-1 acts as a "sponge," trapping VEGF before it can reach the cell surface.
- CVD Outcome: Primary driver of Preeclampsia and linked to heart failure.
2. The "Reawakening" of Fetal Isoforms (Gain of Toxicity)
Endothelial cells under stress revert to immature splicing patterns, including protein segments (exons) normally turned off in adults.
The Protein: Fibronectin (FN)
- Normal Function: Structural protein. Specific segments (Exons EIIIA/EIIIB) are spliced out in healthy adults.
- Splicing Error: In atherosclerosis, the endothelium splices Exon EIIIA back in.
- Endothelial Problem: The EIIIA+ isoform activates TLR4 receptors, mimicking a bacterial infection.
- CVD Outcome: Chronic vascular inflammation fueling Atherosclerosis.
The Protein: Tissue Factor (TF)
- Normal Function: Membrane-bound TF initiates blood clotting upon injury.
- Splicing Error: A soluble splice variant called asTF is produced.
- Endothelial Problem: asTF promotes angiogenesis and attracts immune cells.
- CVD Outcome: Increases instability of atherosclerotic plaques.
3. Summary of Impact
| Disease | Primary Splicing Target | Functional Consequence | Extent of Contribution |
|---|---|---|---|
| Hypertension | eNOS | Loss of vasodilation. | High: Impairs primary blood pressure control. |
| Preeclampsia | Flt-1 (sFlt-1) | Systemic endothelial starvation. | Very High: Central pathogenic driver. |
| Atherosclerosis | Fibronectin (EIIIA) | Activates immune system (TLR4). | Moderate-High: Accelerates plaque instability. |
| Thrombosis | Tissue Factor (asTF) | Promotes inflammation. | Moderate: Modulates plaque vulnerability. |
Yes, your intuition is correct. Reduced acetylation of splicing factors is a significant driver of these endothelial problems, particularly because it makes splicing factors "too sticky."
The Mechanism: Splicing factors (like SRSF1) are naturally positively charged, allowing them to bind to RNA. Acetylation neutralizes this charge, acting as a "release" mechanism. When acetylation is reduced (often due to overactive HDAC enzymes), splicing factors bind too aggressively to the RNA, forcing the inclusion of exons that should have been skipped.
1. The "Sticky Factor" Effect: Fibronectin
- The Mechanism: In healthy cells, splicing factor SRSF1 is acetylated to detach from RNA, skipping Exon EIIIA.
- The Problem (Reduced Acetylation): High levels of HDACs strip acetyl groups off SRSF1.
- The Result: Hypo-acetylated SRSF1 binds avidly to Exon EIIIA, forcing its inclusion.
- Therapeutic Proof: HDAC inhibitors force acetylation back up, stopping the production of the inflammatory isoform.
2. The Angiogenesis Switch: VEGF
- The Mechanism: Endothelial repair (angiogenesis) requires the VEGF-A isoform.
- The Problem: High HDAC activity (low acetylation) suppresses healthy VEGF-A expression.
- The Result: The endothelium cannot repair itself effectively.
- Therapeutic Proof: Increasing acetylation enhances "sprouting" and repair.
3. The "Master Regulator": HDAC Overactivity
The root cause is often the overactivity of HDACs (Histone Deacetylases) in diseased endothelial cells due to oxidative stress. This locks the splicing machinery into a "stress response" mode.
Summary Table: Acetylation Impact
| Target Protein | Condition | Acetylation Status | Splicing Outcome | Result |
|---|---|---|---|---|
| Fibronectin | Atherosclerosis | Reduced (Hypoacetylated) | Inclusion of Exon EIIIA | High Inflammation |
| VEGF | Ischemia/Diabetes | Reduced (Hypoacetylated) | Shift to Anti-angiogenic | Poor Vessel Repair |
| General Splicing | CVD Stress | Reduced (High HDACs) | Rigid/Aberrant binding | Endothelial Dysfunction |
Conclusion: This confirms that HDAC inhibitors might act as cardiovascular drugs by "lubricating" the splicing machinery to release "bad" exons.