Senescence-Induced Oxidative Stress Causes Endothelial Dysfunction.
Age is a risk factor for cardiovascular disease, suggesting a causal relationship between age-related changes and vascular damage. Endothelial dysfunction is an early pathophysiological hallmark in the development of cardiovascular disease. Senescence, the cellular equivalent of aging, was proposed to be involved in endothelial dysfunction, but functional data showing a causal relationship are missing.Endothelium-dependent vasodilation was measured in aortic rings ex vivo. We investigated aortas from aged C57Bl/6 mice (24-28 months), in which p16 (INK4a) and p19 (ARF) expression, markers of stress-induced senescence, were significantly induced compared to young controls (4-6 months). To reflect telomere shortening in human aging, we investigated aortas from telomerase deficient (Terc(-/-)) mice of generation 3 (G3). Endothelium-dependent vasodilation in aged wildtype and in Terc(-/-) G3 mice was impaired. A combination of the superoxide dismutase mimetic 1-Oxyl-2,2,6, 6-tetramethyl-4-hydroxypiperidine (TEMPOL) and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin significantly improved endothelium-dependent vasodilation in aged wildtype and Terc(-/-) G3 mice compared to untreated controls. We show that both, aging and senescence induced by telomere shortening, cause endothelial dysfunction that can be restored by antioxidants, indicating a role for oxidative stress. The observation that cellular senescence is a direct signalling event leading to endothelial dysfunction holds the potential to develop new targets for the prevention of cardiovascular disease.
Department of Pediatric Nephrology, Hepatology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover D-30625, Germany. REBIRTH Excellence Cluster, Hannover Medical School, Hannover D-30625, Germany.
Raj
R
Bhayadia
Department of Nephrology, Hannover Medical School, Hannover D-30625, Germany.
Bernhard M W
BM
Schmidt
Department of Pediatric Nephrology, Hepatology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover D-30625, Germany. REBIRTH Excellence Cluster, Hannover Medical School, Hannover D-30625, Germany.
Anette
A
Melk
Department of Pediatric Nephrology, Hepatology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover D-30625, Germany. REBIRTH Excellence Cluster, Hannover Medical School, Hannover D-30625, Germany.
Meike
M
Hömme
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008168:Lung / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009249:NADP / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013113:Spin Labels; D059506:Telomere Shortening / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects
D000098:Acetophenones; D000975:Antioxidants; D015415:Biomarkers; D003497:Cyclic N-Oxides; D012333:RNA, Messenger; D013113:Spin Labels; D009249:NADP; C056165:acetovanillone; D006861:Hydrogen Peroxide; C001803:tempol
Biology of Aging; Cardiovascular Disease; Cellular Senescence; Endothelial; Mice