The Role of Cellular Senescence in Aortic Dissection

Abstract Background Aortic dissection (AD) is a catastrophic disease with high mortality. Survived patients frequently suffer from serious complications due to progressive destruction of the aortic walls. Recently we have reported that cell proliferation precedes the inflammatory response which is important in AD development and progression. Since cell proliferation promotes cellular senescence that can induce inflammatory response through SASP (senescence-associated secretary phenotype), we hypothesized that cellular senescence plays a critical role in AD pathogenesis. Purpose To investigate if cellular senescence contributes to AD pathogenesis 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 occurs to most of the mice in 14 days. BAPN+AngII challenge resulted in the appearance of senescent cells in the aortic walls before AD onset, which persisted for 14 days. Senescent cells, as demonstrated by the expression of senescence-associated beta-galactosidase, were evident in multiple types including endothelial cells, medial smooth muscle cells, adventitial macrophages and fibroblasts. Rapamycin, an inhibitor of mTOR pathway, suppressed the cell proliferation, the cellular senescence, and the development and progression of AD. To examine the role of cellular senescence in AD pathogenesis, ABT263, which is a senolytic drug that eliminates senescent cells, was administered orally to AD model mice. ABT263 treatment reduced the expression of the senescence markers. In the ABT263-treated group, the AD mortality was significantly decreased compared to that in vehicle-treated group (35% vs 67%, P < 0.05 by log-rank test). The severity of AD, as assessed by the lesion length, was also attenuated in ABT263 group (24.6 ± 1.8 mm vs 33.2 ± 3.1 mm, P < 0.05). Transcriptome analysis revealed that ABT263 treatment suppressed the aortic immune and inflammatory response induced by BAPN+AngII. Quantitative RT-PCR of aortic tissue confirmed that ABT263 treatment prevented the induction of p21, interleukin-6, several chemokines and M1 macrophage marker (CD80). ABT263 treatment suppressed CD80 expression also in cultured macrophages. Conclusions These results indicated that cell proliferation and senescence via mTOR pathway are critically involved in AD pathogenesis. Cellular senescence contributes to the inflammatory response including M1 differentiation of macrophages, and to the severity and the mortality in AD. Cellular senescence could be a new therapeutic target for AD.