TNF-? and IL-1? Up-Regulate MMP-9 Expression in Damaged Dissected Rat Aorta by Mechanical Stretch via ERK1/2/p38/JNK Signaling Pathway Activation

Objective: Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) promote aortic dissection (AD). However, the mech-anisms involved remain unclear. This study evaluated IL-1 beta and TNF-alpha effect on mitogen-activated protein kinase (MAPK) signaling and matrix metalloproteinase 9 (MMP-9) expression in dissected rat aorta receiving mechanical stretch.Methods: Rats were administered with beta-aminopropionitrile to produce an AD model. Dissected aortas were mechanically stretched (3 g) and incubated with TNF-alpha, IL-1 beta, and inhibitors of the c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways (SB203580, U0126, and SP600125, re-spectively). IL-1 beta, TNF-alpha, ERK1/2, phospho-p38 (p-p38), p38, p-ERK1/2, JNK1, p-JNK1, and MMP-9 levels were assessed by immunohistochemical analysis and/or quantitative real-time polymerase chain reaction (qRT-PCR).Results: IL-1 beta, TNF-alpha, p-ERK1/2, p-p38, p-JNK1, and MMP-9 levels increased in the 3 g group relative to the 0 g group (p < 0.05) and were up-regulated by exogenous IL-1 beta and TNF-alpha in both the 0 and 3 g groups (p < 0.05). Treatment with p38/ERK1/2/JNK inhibitors remarkably down-regulated IL-1 beta, TNF-alpha, p-ERK1/2, p-p38, p-JNK1, and MMP-9 in the 3 g + IL-1 beta and 3 g + TNF-alpha groups (p < 0.05). IL-1 beta, TNF-alpha, p-ERK1/2, p-p38, p-JNK1, and MMP-9 levels were significantly lower in the 3 g + SB203580/SP600125/U0126 + IL-1 beta and 3 g + SB203580/SP600125/U0126 + TNF-alpha groups than the 3 g group (p < 0.05).Conclusions: Our data demonstrated that MMP-9 was up-regulated by IL-1 beta and TNF-alpha through ERK1/2/p38/JNK signaling in dissected rat aorta.