Abstract 18920: Post-Translational Modification of Telomeric Repeat-Binding Factor 2 (terf2)-Interacting Protein (terf2ip) Mediates Atherosclerosis (as) via Orchestrating Endothelial Cells (ec) Senescence (sen) and Inflammation
Objective: Shortened telomere (TL) provokes EC Sen, which is associated with focalized EC inflammation and plaque formation in the area exposed by disturbed flow (d-flow). Although it is well known that d-flow increases both EC inflammation and Sen, the exact mechanisms by which d-flow coordinately induces these two different EC pathologies and subsequent AS are poorly understood.
Methods & Results: TERF2IP, as a member of the sheltrin complex, is not only crucial for DNA double strand break repair at the TL, but also for activation of cytosolic IkB kinase (IKK) and subsequent NF-kB activity. TERF2IP and TERF2 form a stable heterodimer to protect the duplex region of TLs, while activating NF-kB, especially under the d-flow condition. We have discovered the critical role of p90RSK activation in regulating d-flow-induced TERF2IP S205 phosphorylation and K240 SUMOylation. The nuclear TERF2IP-TRF2 complex protects TLs by repairing DNA damages while the cytosolic complex plays a role in NF-kB activation. When we mutated the TERF2IP phosphorylation site, the nuclear export of the TERF2IP-TERF2 complex was abolished, which inhibited d-flow-induced both NF-kB activation and Sen.. When TERF2IP SUMOylation was induced by p90RSK overexpression or depletion of de-SUMOylation enzyme SENP2, EC Sen was promoted via TL dysfunction. The depletion of TERF2IP by siRNA inhibited d-flow-induced TERF2 nuclear export, and residual TERF2 at the TL inhibited d-flow-induced TL dysfunction. While cytosolic IKK-NF-kB activation was inhibited by eliminating the cytosolic TERF2IP-TERF2 complex. The inhibition of d-flow-induced inflammatory adhesion molecule expression and consequent AS were also confirmed in EC-specific TERF2IP knock out mice.
Conclusion: These results suggest that PTMs of TERF2IP is required for d-flow-induced TL shortening and NF-kB activation via regulating nuclear export of the TERF2IP-TERF2 complex.
Author Disclosures: N. Le: None. K. Heo: None. K. Ko: None. T. Thomas: None. K. Fujiwara: None. J. Abe: None.
- © 2016 by American Heart Association, Inc.