Abstract 17867: The Pro-angiogenic Long Non-coding Rna Tykril Controls Human Pericyte Function Through Regulation Of P53 Activity and Pdgfrß Expression
Rationale: Pericytes contribute to the formation, maturation and stabilization of blood vessels, making them indispensable for proper cardiovascular organ function. Although long non-coding RNAs (lncRNAs) are pivotal in cardiovascular development, their role in pericytes has so far been neglected.
Objective: Here we assessed the hypothesis that lncRNAs significantly regulate pericyte function.
Methods and Results: Via RNA deep sequencing we show that the hypoxia induced lncRNA TYKRIL (Tyrosine Kinase Receptor Inducing lncRNA) modulates expression of the tumor suppressor p53 and Platelet derived growth factor receptor beta (PDGFRß) in human pericytes. Luciferase reporter arrays demonstrated that silencing of TYKRIL with GapmeRs (0.22+0.04 vs. scramble Ctrl., n=8, P<0.001) significantly enhances activity of p53 (2.9+0.55 fold induction vs. scramble Ctrl., n=3, P=0.0103). TYKRIL knockdown increased acetylation of the p53 lysine residue K382, which is known to be required for p53 activation. TYKRIL silencing downregulated the known p53 target PDGFRß (protein expression: 0.46+0.08 vs. Ctrl., n=4, P<0.001) which consecutively disrupted AKT and ERK1/2 phosphorylation. Thereby, pericyte viability (MTT cell viability: 0.8+0.03 vs. Ctrl., n=3, P<0.01), proliferation (Ki67 proliferation index fold change 0.71+0.05 vs. Ctrl., n=6, P<0.001) and recruitment towards endothelial cells in matrigel co-culture assays was markedly reduced (fold change 0.37+0.03 vs. Ctrl., n=5-7, P<0.001). In turn, silencing of p53 reversed these effects (MTT cell viability: TYKRIL knockdown + scramble 0.7+0.04; TYKRIL knockdown + siRNAp53 0.94+0.04, n=11-12, P<0.01).
In patients with ischemic heart failure (n=18), cardiac TYKRIL and PDGFRß expression are significantly reduced compared to controls (TYKRIL vs. Ctrl. 0.01+0.005, P<0.001; PDGFRß mRNA expression: 0.44+0.11, P<0.05).
Conclusion: Our results identify TYKRIL as a pro-angiogenic lncRNA that is down-regulated by ischemic heart failure and significantly regulates pericyte viability and recruitment towards endothelial cells by repression of p53 activity and stabilization of PDGFRß signalling.
Author Disclosures: C.M. Zehendner: None. A. Werner: None. F. Bischoff: None. J. Boeckel: None. S. Demolli: None. K. Michalik: None. B. Meder: None. H.A. Katus: None. J. Haas: None. W. Chen: None. D. John: None. S. Uchida: None. A.M. Zeiher: None. S. Dimmeler: Consultant/Advisory Board; Modest; Miragen. Research Grant; Significant; ERC, DFG.
- © 2015 by American Heart Association, Inc.