Endothelial cell telomere dysfunction induces senescence and results in vascular and metabolic impairments.

Autor: Bloom SI; Department of Nutrition and Integrative Physiology, The University of Utah, Salt Lake City, Utah, USA., Liu Y; Department of Geriatrics, Tongji Hospital, Wuhan, China.; Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA., Tucker JR; Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA., Islam MT; Department of Nutrition and Integrative Physiology, The University of Utah, Salt Lake City, Utah, USA., Machin DR; Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.; Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, Florida, USA., Abdeahad H; Department of Nutrition and Integrative Physiology, The University of Utah, Salt Lake City, Utah, USA., Thomas TG; Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA., Bramwell RC; Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA., Lesniewski LA; Department of Nutrition and Integrative Physiology, The University of Utah, Salt Lake City, Utah, USA.; Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.; Geriatric Research, Education and Clinical Center, Veteran's Affairs Medical Center-Salt Lake City, Salt Lake City, Utah, USA.; Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, Utah, USA., Donato AJ; Department of Nutrition and Integrative Physiology, The University of Utah, Salt Lake City, Utah, USA.; Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.; Geriatric Research, Education and Clinical Center, Veteran's Affairs Medical Center-Salt Lake City, Salt Lake City, Utah, USA.; Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, Utah, USA.; Department of Biochemistry, The University of Utah, Salt Lake City, Utah, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2023 Aug; Vol. 22 (8), pp. e13875. Date of Electronic Publication: 2023 May 31.
DOI: 10.1111/acel.13875
Abstrakt: In advanced age, increases in oxidative stress and inflammation impair endothelial function, which contributes to the development of cardiovascular disease (CVD). One plausible source of this oxidative stress and inflammation is an increase in the abundance of senescent endothelial cells. Cellular senescence is a cell cycle arrest that occurs in response to various damaging stimuli. In the present study, we tested the hypothesis that advanced age results in endothelial cell telomere dysfunction that induces senescence. In both human and mouse endothelial cells, advanced age resulted in an increased abundance of dysfunctional telomeres, characterized by activation of DNA damage signaling at telomeric DNA. To test whether this results in senescence, we selectively reduced the telomere shelterin protein telomere repeat binding factor 2 (Trf2) from endothelial cells of young mice. Trf2 reduction increased endothelial cell telomere dysfunction and resulted in cellular senescence. Furthermore, induction of endothelial cell telomere dysfunction increased inflammatory signaling and oxidative stress, resulting in impairments in endothelial function. Finally, we demonstrate that endothelial cell telomere dysfunction-induced senescence impairs glucose tolerance. This likely occurs through increases in inflammatory signaling in the liver and adipose tissue, as well as reductions in microvascular density and vasodilation to metabolic stimuli. Cumulatively, the findings of the present study identify age-related telomere dysfunction as a mechanism that leads to endothelial cell senescence. Furthermore, these data provide compelling evidence that senescent endothelial cells contribute to age-related increases in oxidative stress and inflammation that impair arterial and metabolic function.
(© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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