Telomeres, the DNA TTAGGG repeat sequences at the ends of eukaryotic chromosomes, are stabilized by telomerase to serve as protective capping and to prevent degradation. Stem cells constitutively overexpress the catalytic core telomerase reverse transcriptase (TERT) manifesting high levels of telomerase activity, which confers an apparently indefinite lifespan and is rate limiting for tissue renewal. In contrast, the majority of human adult somatic cells are thought to transcriptionally repress TERT resulting in telomere shortening and cellular senescence. Although most adult cells display low basal telomerase activity, mounting evidence indicates that TERT transcription is tightly regulated and inducible in various cell types in response to changes in environmental cues. In human atherosclerosis telomerase is activated and TERT expression correlates with the extent of the disease;however, the mechanisms underlying telomerase activation and the physiological role of inducible TERT expression in atherosclerosis remain to be discovered. Our preliminary studies confirm increased TERT expression in macrophages of human atherosclerotic lesions and telomerase activation during atherosclerosis development.
Two specific aims are proposed to explore the significance of these findings and to test the hypothesis that telomerase is induced in macrophages and contributes to the development of atherosclerosis.
In Specific Aim 1 we will utilize cellular and molecular approaches to determine the transcriptional regulation of TERT activation in macrophages and test the hypothesis that TERT constitutes a NFk _B-regulated target gene in macrophages.
In Specific Aim 2 we will determine the contribution of TERT to the development of atherosclerosis. Ultimately, the results of these studies will not only characterize the mechanisms underlying telomerase activation in atherosclerosis but also advance our understanding of the role of telomerase in atherosclerosis.
Atherosclerotic cardiovascular disease is the leading cause of death in the United States, and inflammatory pathways contribute to all stages of the disease. This application will investigate the mechanisms by which telomerase, an enzyme that generates protective caps at the ends of chromosomes and controls gene expression programs, influences the development of atherosclerosis. The results of these studies may ultimately characterize telomerase-dependent activation of inflammation as a novel pathway contributing to atherosclerosis and improve our understanding of the inflammatory components of atherosclerosis.
| Gizard, Florence; Heywood, Elizabeth B; Findeisen, Hannes M et al. (2011) Telomerase activation in atherosclerosis and induction of telomerase reverse transcriptase expression by inflammatory stimuli in macrophages. Arterioscler Thromb Vasc Biol 31:245-52 |
| Findeisen, Hannes M; Gizard, Florence; Zhao, Yue et al. (2011) Telomerase deficiency in bone marrow-derived cells attenuates angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol 31:253-60 |
