Exercise Modulates Inflammatory, Cytokine, and Growth Factor Pathway Dysregulation in a Mouse Model of Aortic Dissection and Aneurysm

Aerobic exercise can prevent aortopathy in mouse models. The objective of this study was to better understand the mechanisms underlying this finding. Mice treated with β-aminopropionitrile (BAPN), an irreversible inhibitor of lysyl oxidase (LOX) which induces thoracic aortic aneurysm and dissection (TAAD), underwent either a forced moderate treadmill regimen or maintained conventional cage activity without forced exercise. RNA sequencing was utilized to determine the transcriptomic profile of the ascending and thoracic aorta (n=7 per group). BAPN induced overexpression of 357 genes and decreased expression of 77 genes compared with controls. Causal analysis in Ingenuity Pathway Analysis® software using a fold change |2| and FDR < 0.05 revealed that BAPN activates phagosome formation, leukocyte extravasation, phagocytosis, hepatic fibrosis signaling, neuroinflammation signaling, production of nitric oxide and reactive oxygen species in macrophages, leukocyte migration and inflammatory response, among other pathways, in the aorta (z-score > 2, p-value < 0.05). Pathways of the overexpressed upstream regulators TYROBP, IL6, SPI1, IL1B, CCR2, and TGFβ1, among others, were predicted to be activated (z-score > 2, BH p-value of overlap < 0.05). A comparison analysis between the two groups sorted by trend and score demonstrates that moderate aerobic exercise reverses the predicted activation of these pathways. Next, we investigated whether activated TGFβ1 signaling, predicted to be normalized with exercise compared with unexercised mice, is required for the aortopathy caused by LOX inhibition. We administered SB431542, a selective small peptide inhibitor of the TGF-β1 receptor (TGF-β1R), to a separate cohort of BAPN-treated mice. Histologic analysis demonstrated that the addition of the TGF-β1R inhibitor reverses many of the histologic changes characteristic of BAPN-induced aortopathy, including reversal of wall thickening (p < 0.001), elastin degradation (p < 0.01), and cystic medial degeneration (p = 0.04) in the thoracic aorta. While further investigation is necessary, our study suggests that the prevention of TAAD and its complications by moderate aerobic exercise may in part be due to deactivation of the dysregulated TGF-β1 pathway.