The role of cellular senescence on aortic dissection in mice

Background Aortic dissection (AD) is a catastrophic disease with high mortality. Recently we reported that cell proliferation precedes the aortic inflammation which is important in AD development and progression. Since cell proliferation induces cellular senescence that is associated inflammatory response, we hypothesized that cellular senescence may contribute to 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 14 days-infusion of beta-aminopropionitrile and angiotensin II (BAPN+AngII), where AD stared to occur from day 7 of BAPN+AngII infusion. BAPN+AngII challenge induced expression of p16Ink4a, a senescence marker, before AD onset and persisted for 14 days. Rapamycin, an mTOR pathway inhibitor, diminished cellular proliferation and senescence. Spatial transcriptome analysis revealed that BAPN+AngII induced expression of proliferation and senescence markers such as cyclins, cyclin-dependent kinase inhibitors, and GLS in aortic wall and surrounding tissue. Senescent cells were evident in multiple types of cells including intimal endothelial cells, medial smooth muscle cells, adventitial macrophages and fibroblasts, as demonstrated by the expression of senescence-associated beta-galactosidase and immunostaining of cell type markers. ABT263, a senolytics, was administered orally to AD model mice to eliminate senescent cells. ABT263 treatment reduced the expression of the senescence markers, the AD mortality (vehicle vs. ABT263; 67% vs. 35%, P < 0.05), and the severity of AD, as assessed by the lesion length (33.2 ± 3 mm vs. 1 24.6 ± 1.8 mm, P < 0.05). Transcriptome analysis revealed that ABT263 administration 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 CD80, a marker of M1 macrophage. In cultured macrophages, ABT263 suppressed protein expression of CD80. Conclusions Cellular senescence contributes to AD progression and mortality, associated with enhancement of inflammatory response and macrophage differentiation into M1 in mice. Cellular senescence was suppressed by the inhibitor of mTOR pathway. Cellular senescence could be a new therapeutic target for AD.