Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and proapoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.

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Aortic dissection (AD) is a serious clinical condition that is unpredictable and frequently results in fatal outcome. Although rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has been reported to be effective in preventing aortopathies in mouse models, its mode of action has yet to be clarified. A mouse AD model that was created by the simultaneous administration of β-aminopropionitrile (BAPN) and angiotensin II (AngII) for 14 days. Rapamycin treatment was started either at day 1 or at day 7 of BAPN+AngII challenge, and continued throughout the observational period. Rapamycin was effective both in preventing AD development and in suppressing AD progression. On the other hand, gefitinib, an inhibitor of growth factor signaling, did not show such a beneficial effect, even though both rapamycin and gefitinib suppressed cell cycle activation in AD. Rapamycin suppressed cell cycle-related genes and induced muscle development-related genes in an AD-related gene expression network without a major impact on inflammation-related genes. Rapamycin augmented the activation of Akt1, Akt2, and Stat3, and maintained the contractile phenotype of aortic smooth muscle cells. These findings indicate that rapamycin was effective both in preventing the development and in suppressing the progression of AD, indicating the importance of the mTOR pathway in AD pathogenesis.

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. FUNDunding Acknowledgement Type of funding sources: None.

Background Aortic dissection (AD) is one of the destructive and fatal aortic diseases, for which molecular pathogenesis is largely unknown. Recent studies have highlighted the importance of inflammatory response in AD. We and others reported that B cells and immunoglobulins participate in pathogenesis of abdominal aortic aneurysm, another form of aortic destructive disease, by promoting inflammatory response. It is not known whether and how B cells participate in AD pathogenesis. Methods and results Immunohistochemical staining of human AD tissue revealed that B cells were clustered together with T cells, macrophages and neutrophils at the entry site of AD with medial disruption. B cell cluster was also observed at the site of medial disruption in mouse model of AD that was induced by continuous infusion of beta-aminopropionitrile and angiotensin II (BAPN+AngII). In muMT mouse, which is deficient for B cells and immunoglobulins due to genetic deletion of immunoglobulin heavy chain, BAPN+AngII induced significantly less severe AD compared to that in wild type. Depositions of IgG and fibrinogen, one of the endogenous antigen for natural IgG, were observed after BAPN+AngII infusion before and after AD development in wild type mice. Deposition of fibrinogen was also observed in mMT mice after BAPN+AngII infusion. The rate of aortic rupture and sudden death was approximately 42% in wild type mice, while that in muMT mouse was 12% (P<0.05). Administration of mouse normal polyclonal IgG to muMT mice resulted in dramatic increase in aortic rupture and sudden death, starting at day 7 of BAPN+AngII infusion, and reaching 69% of rupture rate, indicating the critical role of IgG in AD. Conclusion These findings demonstrated B cells and IgG are critically involved in the destructive inflammation of AD pathogenesis. Further, the deposition of fibrinogen, one of the targets of natural IgG, precedes the development of AD. Our findings may provide the conceptual foundation of the diagnostic strategy for on-going tissue destruction and for the therapeutic opportunities to intervene the progressive tissue destruction in AD. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Japan Society for the Promotion of Science