BACKGROUND AND OBJECTIVE

Epidemiological evidence suggests that the antidiabetic drug metformin (MET) can also inhibit abdominal aortic aneurysm (AAA) formation. However, the underlying protective mechanism remains unknown. It has been reported that phosphorylated AMP-activated protein kinase (AMPK) levels are significantly lower in AAA tissues than control aortic tissues. AMPK activation can inhibit the downstream signaling molecule called mechanistic target of rapamycin (mTOR), which has also been reported be upregulated in thoracic aneurysms. Thus, blocking mTOR signaling could attenuate AAA progression. MET is a known agonist of AMPK. Therefore, in this study, we investigated if MET could inhibit formation of AAA by activating the AMPK/mTOR signaling pathway.

MATERIALS AND METHODS

The AAA animal model was induced by intraluminal porcine pancreatic elastase (PPE) perfusion in male Sprague Dawley rats. The rats were treated with MET or compound C (C.C), which is an AMPK inhibitor. AAA formation was monitored by serial ultrasound. Aortas were collected 4 weeks after surgery and subjected to immunohistochemistry, Western blot, and transmission electron microscopy analyses.

RESULTS

MET treatment dramatically inhibited the formation of AAA 4 weeks after PPE perfusion. MET reduced the aortic diameter, downregulated both macrophage infiltration and matrix metalloproteinase expression, decreased neovascularization, and preserved the contractile phenotype of the aortic vascular smooth muscle cells. Furthermore, we detected an increase in autophagy after MET treatment. All of these effects were reversed by the AMPK inhibitor C.C.

CONCLUSION

This study demonstrated that MET activates AMPK and suppresses AAA formation. Our study provides a novel mechanism for MET and suggests that MET could be potentially used as a therapeutic candidate for preventing AAA.