Abstract 12818: The Role of Cellular Senescence in Aortic Dissection

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. Currently, pathogenesis of AD is largely unknown, which hampers the development of effective approaches to predict the prognosis and to alleviate the progression of AD. Previous studies revealed the importance of inflammation in AD pathogenesis. Recently we found that cell proliferation occurs during the development and the progression of AD. Because cell proliferation triggers cellular senescence, which is associated with secretion of proinflammatory cytokines, we hypothesized that cellular senescence might be involved in AD pathogenesis. Objective: We investigated if cellular senescence contributes to AD development and progression in a mouse AD model. 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 in most of the mice within 14 days. 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. Cellular senescence occurred in one day of BAPN+AngII infusion and was sustained 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 was 16.6±6.9mm, whereas that in ABT263 group was 12.2±4.2 mm (P < 0.05). Conclusions: These findings demonstrated that cellular senescence precedes AD development, and elimination of senescent cells 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.