Abstract 9556: Role of Telomere in Endothelial Dysfunction in Type 2 Diabetic Mice
Type 2 diabetes (T2D) is characterized by shorter telomeres in peripheral blood cells. We examined telomere morphology and confirmed they are also shortened in the T2D vasculature and proceeded to investigate whether telomere shortening acts as a mechanism contributing to vascular complications under metabolic disorders. We hypothesized that vascular telomere dysfunction accelerates early vascular aging and leads to endothelial dysfunction in T2D. To test this, we examined the aortic endothelial function, the expression of telomere-associated proteins, telomerase activity, telomere length, and vascular apoptosis in the aortas of control mice (m Leprdb) and T2D mice (Leprdb) at 3 and 10 months of age (n=6 mice). The expression of telomere-associated protein TRF2 and telomerase activity were reduced, and telomeres were shortened in the aortas of 3-month and 10-month Leprdb vs. 3-month control mice. However, TRF2 expression, telomerase activity and telomere length were not altered in 10-month control mice. The aortic expression of apoptosis regulator Chk2, caspase 3/7 activity and apoptotic cell numbers were elevated in 3-month and 10-month Leprdb, but not in 10-month control mice. Acetylcholine-induced endothelium-dependent vasorelaxation of aortas was impaired in 3-month and 10-month Leprdb, but was normal in 10-month control mice. The aortic endothelial function, telomerase activity and telomere length were not statistically different between 3-month and 10-month Leprdb, suggesting an early vascular aging in type 2 diabetic mice. In cultured mouse coronary artery endothelial cells, incubation at high glucose concentration (30 mmol/L) for 48 hours significantly reduced the mRNA expression of telomerase reverse transcriptase (TERT), supporting the potential role of hyperglycemia in telomere malfunction. We postulated that decreased telomere-associated protein expression and reduced telomerase activity lead to telomere shortening, which is a marker of telomere malfunction. Telomere malfunction contributes to the vascular apoptosis and impairs vasodilatory response in type 2 diabetic mice. In conclusion, telomere dysfunction plays an important role in diabetes-associated early vascular aging and endothelial dysfunction.
- © 2011 by American Heart Association, Inc.