Oxidative Stress, Telomere Shortening, and Cellular Senescence in Aortic Aneurysm

Senescent cells accumulate in tissues throughout the body with age. Their pro-inflammatory, pro-growth signaling is disruptive of tissue structure and function, and has been implicated in the development of aneurysms. An aneurysm is a weakened area of the blood vessel wall, expanding under pressure to form a pocket vulnerable to rupture. This can be fatal, depending on location, such as in a major artery or the brain. Researchers here look at aortic tissues and find raised levels of oxidative signaling, shorter telomeres, and more cellular senescence in these tissues where aneurysms are present.

Aortic aneurysms are characterized by local inflammation with degeneration around the aorta, leading to vessel weakening and dilatation. Degenerative remodeling in the medial layer of aortic aneurysm tissue is characterized by loss of vascular smooth muscle cells (vSMC) and destruction of the extracellular matrix (ECM). This medial degeneration leads to weakening and progressive dilatation of the vascular wall, and ultimately results in aortic dissection or aneurysm rupture.

Telomere shortening is a predictor of age-related diseases, and its progression is associated with premature vascular disease. The aim of the present work was to investigate the impacts of chronic hypoxia and telomeric DNA damage on cellular homeostasis and vascular degeneration of thoracic aortic aneurysm (TAA). We analyzed healthy and aortic aneurysm specimens (215 samples) for telomere length, chronic DNA damage, and resulting changes in cellular homeostasis, focusing on senescence and apoptosis.

Compared with healthy thoracic aorta, patients with tricuspid aortic valve (TAV) showed telomere shortening with increasing aneurysm size, in contrast to genetically predisposed bicuspid aortic valve (BAV). In addition, telomere length was associated with chronic hypoxia and telomeric DNA damage and with the induction of senescence-associated secretory phenotype (SASP). Aneurysm in TAV specimens showed a significant difference in SASP-marker expression of IL-6, NF-κB, mTOR, and cell-cycle regulators (γH2AX, Rb, p53, p21), compared to healthy thoracic aorta and and aneurysm in BAV. We conclude that chronic hypoxia is associated with telomeric DNA damage and the induction of SASP in a diseased aortic wall, promising a new therapeutic target.

Link: https://doi.org/10.3390/ijms232415498