Abstract P121: Vascular Protective Effects of Telomerase Activity Are Independent of Nuclear Function

Abstract

Rationale: The contributions of nuclear telomerase activity to cardiovascular protection we have previously described are not defined. We used a novel inhibitor of nuclear telomerase activity (nucTERT I) to test the hypothesis that nuclear telomerase activity is not critical to the protective effects of telomerase. Methods and Results: To confirm the effect of nucTERT I cultured cells were treated for 24 h and subjected to standard cell fractionation procedures. Telomerase activity (TRAP assay) confirmed decreased nuclear telomerase activity after treatment. nucTERT I reduced nuclear telomerase activity (44% +/- 7) compared to untreated control. To evaluate the effect of nucTERT I on vascular function, human microvessels were dissected from discarded surgical tissue from patients with no history of coronary artery disease and used for videomicroscopy. Vessels were challenged with ANG II and their ability to dilate in response to flow and acetylcholine was evaluated. Vessels pre-treated with nucTERT I (24 h) were significantly less sensitive to ANG II- induced endothelial dysfunction when stimulated with either acetylcholine or increased flow. The telomerase activity inhibitor, BIBR1532, abrogated these effects (figure). Conclusions: Our data suggest that nuclear telomerase activity is not necessary for the protective effects of telomerase on ANG II induced endothelial dysfunction. Treatment with BIBR1532 confirms that vascular stress resistance is conferred by catalytically active telomerase. These data suggest that modulation of telomerase may be a useful strategy in the treatment of vascular disease.