SIRT6 promotes angiogenesis by enhancing VEGFA secretion via demyristoylation in endothelial cell.
Summary
Endothelial SIRT6 promotes angiogenesis by demyristoylating VEGFA, thereby enhancing its secretion under hypoxia and improving endothelial migration and tube formation. Loss of SIRT6 reduces angiogenic responses, and SIRT6 overexpression rescues ALK14-induced defects, highlighting demyristoylation (not deacetylation) as the key activity.
Key Findings
- Endothelial SIRT6 knockout attenuated angiogenesis in mice; SIRT6 promoted endothelial migration and tube formation in vitro.
- SIRT6 regulates intracellular VEGFA levels and global protein myristoylation under hypoxia; knockdown or ALK14 reduced VEGFA secretion.
- CLICK-IT assays identified VEGFA as a myristoylated substrate of SIRT6; SIRT6 enhances VEGFA secretion via demyristoylation, not deacetylation.
- SIRT6 overexpression rescued endothelial angiogenic defects induced by ALK14 treatment.
Clinical Implications
Targeting SIRT6 demyristoylase activity could modulate therapeutic angiogenesis in ischemic heart disease and peripheral ischemia. It also raises caution that broad SIRT6 modulation may affect VEGFA biology.
Why It Matters
This study uncovers a previously unrecognized post-translational mechanism—SIRT6-mediated demyristoylation of VEGFA—linking epigenetic enzyme activity to angiogenesis, suggesting a new therapeutic axis for ischemic cardiovascular disease.
Limitations
- Preclinical study without human validation
- Extent of in vivo models and long-term safety of targeting SIRT6 not addressed
Future Directions
Translate findings to human tissues and ischemic models; develop selective SIRT6 demyristoylase modulators; evaluate therapeutic angiogenesis and safety in large-animal models.
Study Information
- Study Type
- Basic/Mechanistic Research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence without clinical outcomes
- Study Design
- OTHER