Abstract 16105: Long Non-coding RNA TYKRIL Regulates Pericyte Survival in the Cardiovascular and Central Nervous System in vivo in a p53 Dependent Manner
Background: Vessel maturation is dependent on platelet derived growth factor (PDGF), which signals via tyrosine kinase receptors and facilitates recruitment of pericytes. Long noncoding RNAs (lncRNAs) regulate endothelial and smooth muscle cell properties, but their role in pericyte function is unclear.
Hypothesis: Here we assessed the hypothesis that lncRNA TYKRIL (Tyrosin kinase receptor inducing lncRNA) regulates pericyte survival.
Results and Discussion: Using RNA sequencing, we identify the hypoxia induced lncRNA TYKRIL as a species conserved lncRNA which regulates pericyte survival in vitro and in vivo. Using RNA immunoprecipitation (RIP) we demonstrate that TYKRIL binds to p53 (TYKRIL enrichment fold change (FC) 2.7±0.27 vs Ctrl. P<0.001, n=3) and acts as a p53 decoy that blocks interaction of p53 with its co-activator p300 by binding to the N-terminus of p53.
TYKRIL loss fostered p53-p300 interaction in proximity ligation assays (3.57±0.5 FC vs Ctrl., P<0.001, n=3), whereas RNA guided gene activation of TYKRIL reversed this effect (0.6±0.08 FC vs Ctrl., P<0.01, n=4). TYKRIL knockdown downregulated the known p53 target PDGF Receptor ßeta (PDGFRß) (0.46±0.09 FC vs. Ctrl, P<0.01, n=4), and was accompanied by pericyte loss, whilst TYKRIL overexpression fostered PDGFRß expression (1.75±0.21 FC vs. Ctrl, P<0.05, n=3).
Targeting the murine TYKRIL orthologue in the CNS in vivo by LNA GapmeRs resulted in pericyte loss in the cerebral cortex (0.4±0.09 FC vs. Ctrl, P<0.001, n=6) and caused neurological dysfunction (neurological dysfunction score 2.33±0.56 vs. Ctrl, P<0.05, n=6). Moreover, systemic TYKRIL silencing resulted in a loss of PDGFRß expressing pericytes in the myocardium (0.79±0.06 FC vs Ctrl, P<0.05, n=5). Finally, we show significant interdependence of TYKRIL and PDGFRß in cardiac tissue from patients diagnosed with heart failure, as well as in glioblastoma multiforme.
Conclusion: Here, we identify the lncRNA TYKRIL as a p53 decoy molecule that represses p53 activation, thereby regulating pericyte survival in vitro and in vivo. Our results identify TYKRIL as a regulator of pericyte function, which may enable to develop novel concepts for pro- or anti-angiogenic therapies in cardiovascular disease and malignancy.
Author Disclosures: C.M. Zehendner: None. S.C. Thal: None. A. Werner: None. J. Boeckel: None. F. Bischoff: None. D. John: None. T. Weirick: None. N. Jaé: None. S. Demolli: None. R. Hummel: None. K. Michalik: None. B. Meder: None. H.A. Katus: None. J. Haas: None. W. Chen: None. S. Uchida: None. A.M. Zeiher: None. S. Dimmeler: None.
- © 2016 by American Heart Association, Inc.