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Arteriosclerosis, Thrombosis, Vascular Biology
Session Title: Best of Basic Science Posters

Abstract 11655: The Telomerase Plays a Pivotal Role in Collateral Development Under Ischemia by Suppressing Aging-Induced Production of Oxidative Stress, Expression of p53 and Pro-Apoptotic Proteins

Originally publishedCirculation. 2018;138:A11655

    Backgrounds: Aging is a major risk factor for impairment of collateral growth under ischemia, but the contribution of telomerase activity, which is mainly regulated by telomerase reverse transcriptase component (TERT), remains unclear.

    Methods and Results: Unilateral hindlimb ischemia was generated in old (80 week old) and young (8 week old) mice. A telomerase activator, TA-65 (20 μg/kg/day] was orally administered from pre-operative day 21 to post-operative day (POD) 21. Doppler blood flow and capillary density in ischemic hindlimbs on POD 21 were lower in old mice than those in young mice. TA-65 increased both of them by 47% and 43%, respectively. On POD 1 and 3, expressions of TERT and telomerase activity under ischemia in old mice were low compared to those in young mice, which were upregulated with TA-65 treatment. On POD 3, the levels of reactive oxygen species (ROS) measured by fluorescenece plate reader, DNA double-strand breaks, expressions of p53, p21 and p16, and the ratio of Bax/Bcl-2 were elevated in ischemic muscles of old mice compared to young mice. TA-65 treatment decreased the levels of ROS and DNA double-strand breaks on POD3, and maintained the expression of p53, p21 and p16 and the ratio of Bax/Bcl-2 at low levels equivalent to those in young mice until POD 21. Finally, the expression of HIF1-α and VEGF on POD 3 were decreased in old mice compared to young mice, which were upregulated by TA-65.

    Conclusions: Collateral growth under ischemic condition is impaired in aged animals due to low telomerase activity, increased ROS and the resultant DNA damage, and increased expressions of tumor suppressor and pro-apoptotic proteins. These data suggest that telomerase plays a pivotal role in collateral development and its pharmaceutical activation may be a novel therapeutic option to enhance collateral growth and rescue ischemic tissue in old individuals.


    Author Disclosures: T. Kokubun: None. S. Saitoh: None. S. Miura: None. T. Ishida: None. Y. Takeishi: None.


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