Methamphetamine induces thoracic aortic aneurysm/dissection through C/ EBP?

Aims: Thoracic aortic aneurysm/dissection (TAAD) is a life-threatening disease with diverse clinical manifestations. Although the association between methamphetamine (METH) and TAAD is frequently observed, the causal relationship between METH abuse and aortic aneurysm/dissection has not been established. This study was designed to determine if METH causes aortic aneurysm/dissection and delineate the underlying mechanism. Methods and results: A new TAAD model was developed by exposing METH to SD rats pre-treated with lysyl oxidase inhibitor beta-aminopropionitrile (BAPN). Combination of METH and BAPN caused thoracic aortic aneurysm/dissection in 60% of rats. BAPN+METH significantly increased the expression and activities of both matrix metalloproteinase MMP2 and MMP9, consistent with the severe elastin breakage and dissection. Mechanistically, METH increased CCAAT-enhancer binding protein beta (C/EBP beta) expression by enhancing mothers against decapentaplegic homolog 3 (Smad3) and extracellular regulated protein kinase (ERK1/2) signaling. METH also promoted C/EBP beta binding to MMP2 and MMP9 promoters. Blocking C/EBP beta significantly attenuated METH+BAPN-induced TAAD and MMP2/MMP9 expression. Moreover, BAPN+METH promoted aortic medial smooth muscle cell (SMC) apoptosis through C/EBP beta-mediated IGFBP5/p53/PUMA signaling pathways. More importantly, the expression of C/EBP beta, MMP2/MMP9, and apoptosis-promoting proteins was increased in the aorta of human patients with thoracic aortic dissection, suggesting that the mechanisms identified in animal study could be relevant to human disease. Conclusions: Our study demonstrated that METH exposure has a casual effect on TAAD. C/EBP beta mediates METHintroduced TAAD formation by causing elastin breakage, medial cell loss and degeneration. Therefore, C/EBP beta may be a potential factor for TAAD clinical diagnosis or treatment.