Vildagliptin, a dipeptidyl peptidase-4 inhibitor, ameliorates the development of CaCl2-induced abdominal aortic aneurysm in mice via anti-inflammatory effects

Background: Abdominal aortic aneurysm (AAA) is characterized by the destruction of tissue architecture due to chronic inflammation of unknown etiology. Recent studies showed that dipeptidyl peptidase-4 (DPP4) inhibitors, which increase circulating glucagon-like peptide-1 (GLP1) level, have vascular protective effects. We investigated the potential effect of vildagliptin, a DPP4 inhibitor, on the development of AAA. Methods: For induction of AAA, we applied 0.5 M CaCl2 to the infrarenal aorta, then mice received vildagliptin (30mg/kg/day, n=10) or a vehicle (n=10) with oral administration for six weeks. Saline-treated mice were served as controls (n=10). Incidence of AAA was defined as external diameter >1.5 fold of the averege of the control group. The expressions of mRNA were analyzed by real-time quantitative PCR using aortic tissue after one week CaCl2 treatment. Matrix metalloproteinase (MMP) activity was detected by gelatin zymography. Results: Six week after application of CaCl2, AAA was observed in 70% of the vehicle group; however, oral administration of vildagliptin strikingly decreased the incidence of AAA by 30% (p<0.01) (external diameters; 1113±185 μm [vehicle] vs. 946±154 μm [vildagliptin] vs. 642±59 μm [Saline], p<0.05, respectively). Histological analysis showed that the recruitment of macrophages into AAA lesion in the vehicle group was significantly greater than that in the vildagliptin group (3.3±2.0 cell/μm2 vs. 2.2±2.2 cell/μm2, p<0.05). Quantitative PCR demonstrated that the elevated expressions of MMP-2, -9, -12 and monocyte chemotactic protein-1 in vehicle group at one week after CaCl2 treatment were significantly decreased in the vildagliptin group. In addition, mRNA expression of Hspa5 as a marker of Endoplasmic reticulum (ER) stress and p47phox as a marker of oxidative stress were also reduced in the vildagliptin group. The activities of MMP-2 and -9 determined by gelatin zymography were significantly reduced in the vildagliptin group compared with the vehicle group. In vitro experiments, physiological levels of GLP-1 did not suppressed MMP-9 production and proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha production from macrophages (RAW264.7) in response to lipopolysaccharide (LPS), but co-incubation of macrophages with vildagliptin and physiological levels of GLP-1 significantly suppressed LPS-induced inflammation by 70-80%. Conclusion: Vildagliptin attenuated the development of CaCl2-induced AAA in mice. Anti-inflammatory effects through augmenting GLP-1 activity in macrophages may contribute to the protection of AAA.