The role of cellular senescence in aortic dissection

Abstract

Abstract Background Aortic dissection (AD) is a catastrophic disease that occurs suddenly. The acute mortality is high and those who survived frequently suffer from serious complications such as aneurysm formation and distal ischemia due to progressive destruction of the aortic walls. Currently, no reliable predictor is available for AD development and surgical intervention is the only therapeutic option to prevent the fatal events after AD development, because the pathogenesis of AD is largely unknown. Clinical and experimental studies highlighted the importance of inflammation in AD pathogenesis, although the trigger of inflammation remains unclear. Recently, we found that cell proliferation precedes the inflammatory response in AD. Because cell proliferation triggers cellular senescence and senescent cells secrete of proinflammatory cytokines and matrix metalloproteinases, we hypothesized that cellular senescence may participate in AD pathogenesis. Objective We investigated if cellular senescence contributes to AD development and progression in a mouse model of AD. Methods and results A mouse AD model was created by continuous infusion of beta-aminopropionitrile and angiotensin II (BAPN+AngII), where AD starts to develop in 3 days and occurs to most of the mice in 14 days accompanied by frequent AD rupture and death. Infusion of BAPN+AngII resulted in the appearance of senescent cells that are positive for senescence-associated beta-galactosidase, and expression of senescence markers Arf and Ink4a in the aortic walls. Appearance of cellular senescence occurred in one day of BAPN+AngII infusion and continued throughout the observational period of 14 days. We examined the role of cellular senescence in AD pathogenesis by oral administration of ABT263 which is known as “senolytics” that eliminates senescent cells. ABT263 treatment reduced the expression of the senescence markers. In the vehicle-treated group, the mortality was 66.7% (12/18), whereas that of ABT263-treated group was 35% (14/20, P<0.05 by log-rank test). The severity of AD, as assessed by the lesion length in vehicle group was33.2±3.1 mm, whereas that in ABT263 group was 24.6±1.8 mm (P<0.05). Conclusions These findings demonstrated that cellular senescence precedes AD development, and ABT263 effectively prevented AD progression and death, indicating the involvement of cellular senescence in AD pathogenesis. Therefore, cellular senescence represents a potential predictor and a therapeutic target for AD. Funding Acknowledgement Type of funding sources: None.