Disturbed flow-induced TERF2IP post-translational modifications and atherosclerosis.

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 DESCRIPTION (provided by applicant): Endothelial cell (EC) dysfunction and vasculopathy play a key role in pathogenesis of atherosclerosis (AS). In addition to EC inflammation, senescence (Sen) may play a role in EC dysfunction. Telomere (TL) shortening and dysfunction provokes EC Sen, which is associated with focalized plaque formation. Although it is well known that disturbed flow (d-flow) increases both EC inflammation and Sen, the exact mechanisms by which d-flow uniquely induces these two different EC pathologies and subsequent AS are poorly understood. To answer the question of how d-flow leads to EC inflammation and Sen simultaneously, we developed in vivo and in vitro models for studying signaling induced by d-flow and found unique roles for p90RSK kinase and telomeric repeat-binding factor 2 (TRF2)-interacting protein (TERF2IP) and TRF2 complex in this mechanism. The TERF2IP-TRF2 complex is known to be involved in regulation of double strand break (DSB) repair of DNA at TLs as a component of the shelterin complex and of NF-κB signaling outside in the cytosol. In our preliminary studies, we found that d-flow induced p90RSK activation and up-regulated TERF2IP S205 phosphorylation and K240 SUMOylation in ECs. These TERF2IP posttranslational modifications were mediated by p90RSK activation, and overexpression of a kinase-dead mutant of p90RSK (KD-p90RSK), a TERF2IP S205A phosphorylation mutant, or a TERF2IP K240R SUMOylation mutant inhibited d-flow-induced Sen and DNA damage in ECs. Our central hypothesis is that d-flow-induced EC p90RSK activation, which increases TERF2IP phosphorylation and SUMOylation, elicits TL dysfunction by modifying the function of the TERF2IP-TRF2 complex, leading to EC dysfunction and ultimately to AS. We propose the following 3 aims to identify the mechanisms of TERF2IP-dependent EC dysfunction. Aim 1 will test the hypothesis that TERF2IP phosphorylation causes nuclear export of the TERF2IP-TRF2 complex and subsequent TERF2IP SUMOylation reduces the TL protection activity of the complex. Aim 2 will investigate whether TERF2IP phosphorylation is crucial for up-regulating EC inflammation. In Aim 3, we will determine the role of the p90RSK-TERF2IP module in regulating EC function and AS plaque formation in vivo. Although the possible involvement of EC Sen in AS has been suggested, to our knowledge there has been no study on the role of shelterin complex in AS formation. The new knowledge on the pathways activated by d-flow that alter EC TL function will aid development of new therapeutic strategies for AS, especially by inhibiting p90RSK-mediated TERF2IP post- translational modifications.