Abstract 15649: Terf2ip K240 Sumoylation Drives Endothelial Senescence and Atherogenesis via Activating Parp1

The goal of this study: Telomeric repeat-binding factor 2 (TRF2) interacting protein 1 (TERF2IP) not only associates with TRF2 to protect telomeres but also associates with RSK to promote senescence. The later has been detected in endothelial cells (ECs) under disturbed flow (DF), which involved TERF2IP S205 phosphorylation. Besides, it has been suggested that TERF2IP K240 can be SUMOylated; however, its role in senescence and atherogenesis remains unknown. Methods: We investigated the functional role of TERF2IP K240 SUMOylation utilizing a model of DF-induced atherogenesis in TERF2IP K237R knock-in (KI) (mouse K237 is equivalent to human K240) mouse carotid artery by partial ligation and RNA isolated from mouse lung ECs. Results: TERF2IP K240 SUMOylation was increased in ECs under DF and provoked telomere shortening-associated senescence. TERF2IP K240 SUMOylation occurred independently of TERF2IP S205 phosphorylation although both events were blunted by the RSK specific inhibitor (FMK-MEA), and EC senescence as well as related events were abolished by both depletion and point mutation of TERF2IP at S205 or K240 residue. Whereas point mutation of TERF2IP at S205 prevented RSK-associated NF-kB activation, that of K240 exhibited no effect, suggesting that K240 SUMOylation did not involve in EC inflammation. By inducing persistent telomere DNA damage, TERF2IP K240 SUMOylation distinctive provoked telomere shortening-associated EC senescence via inducing persistent DNA damage response and subsequent PARP1 activation. Finally, a mouse model of DF-induced atherogenesis showed that atherogenesis was inhibited in TER2IP K237R KI mice although body weight and cholesterol level were unaltered Discussions: These data have revealed that EC senescence plays a critical role in atherogenesis and that TERF2IP K240 SUMOylation can be a novel therapeutic target for atherogenesis.