{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:00:11Z","timestamp":1790312411449,"version":"4.1.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Endothelial dysfunction is a hallmark of atherosclerosis, driven by chronic exposure to oxidized LDL and linked to impaired autophagy. Although restoring autophagy in atherosclerosis has been shown to yield protective effects, the mechanisms contributing to dysregulated autophagy are unknown. Apart from previously known extra telomeric role in regulating inflammation, emerging evidence suggests a strong direct correlation between hTERT and autophagy pathway, however, potential molecular mechanisms still remain unknown. This study investigates hTERT's extra-telomeric function in rescuing oxLDL-induced endothelial dysfunction via autophagy regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>hTERT was ectopically overexpressed or knocked down in oxLDL treated HUVEC cells to study its effect in endothelial dysfunction using oxLDL retention, monocyte attachment, endothelial resistance and barrier breach assays. Autophagy-related gene expression and autophagy dynamics were evaluated through qPCR, western blotting, live-cell imaging, immunofluorescence, and co-immunoprecipitation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>OxLDL-induced endothelial dysfunction reduced hTERT expression and increased ICAM1 levels. Pharmacological inhibition of hTERT with MST312 upregulated ICAM1 indicating induction of endothelial dysfunction. Ectopic hTERT expression rescued endothelial dysfunction, demonstrated by reduced intracellular oxLDL levels, decreased monocyte adhesion, improved barrier integrity, and increased TEER. Conversely, hTERT knockdown exacerbated these dysfunction markers. Mechanistically, hTERT enhanced autophagy gene expression and kinetics, with hTERT blockade reducing lysosome abundance. hTERT colocalized and associated with Rab7A under basal conditions, with enhanced association following oxLDL exposure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study highlights a novel additional role of extra telomeric hTERT in contributing to endothelial resilience against atherogenic stress by rescuing endothelial dysfunction via enhancing the expression of autophagy-related gene expression and enhancing autophagy dynamics by associating with Rab7A.<\/jats:p>\n                  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