Inhibitory effects of doxycycline on the onset and progression of abdominal aortic aneurysm and its related mechanisms

The objective of this study was to investigate whether doxycycline (DOX) given at different doses and via different administration routes had protective or therapeutic effects on abdominal aortic aneurysm (AAA) induced by elastase in mice. Moreover, the anti-AAA mechanism of DOX was studied in TNF-a-stimulated vascular smooth muscle cell (VSMC) in vitro. For in vivo study, either daily administration of 30 mg/kg of DOX by gavage or intraperitoneal injection of 15 mg/kg DOX every other day for 14 days significantly prevented the development of AAA at its early stage. Further study showed that intraperitoneal injection of 15 mg/kg DOX every other day for 7 times in total could also cure the established AAA. In vitro study showed that treating VSMCs with TNF-alpha together with DOX remarkably inhibited the expressions and activities of MMPs (MMP-2 and MMP-9), significantly suppressed the activation of protein kinase B (AKT) signaling pathway and mitogen activated protein kinases (MAPKs) signal proteins, including extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinases (JNK) and p38, and downregulated mRNA levels of interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1), and significantly upregulated mRNA levels of transforming growth factor beta (TGF-beta), heme oxygenase 1 (HO-1) and superoxide dismutase 1 (SOD-1), indicating that DOX inhibits activities of MMPs through reducing oxidative stress, suppressing MAPKs and AKT signaling pathways and ameliorating inflammation in VSMCs, and therefore, exerts preventive as well as therapeutic effects on AAA.