Abstract 101: Dipeptidylpeptidase-iv Inhibition Using MK626 Attenuates BAPB/AT2 Induced Murine Aneurysm

The dearth of effective treatments to diminish aneurysm progression is a recognized clinical challenge. Modulation of the glucagon-like peptide-1 (GLP-1) pathway is a recent addition to anti-diabetic management regimes, and has pleiotropic effects to inhibit arterial wall macrophage infiltration, a key pathological event in aneurysmal disease. We therefore hypothesized that inhibition of endogenous breakdown of GLP-1, using the dipeptidylpeptidase-IV inhibitor MK626, would attenuate BAPN/AT2 induced murine aneurysm. Eight-week-old C57/Bl6 mice received two weeks of oral beta-aminopropriononitrile (BAPN) and four weeks of angiotensin-2 (AT2) via mini-osmotic pump. MK626 3mg/kg in methylcellulose vehicle was administered daily and compared to control methylcellulose vehicle. At four weeks, whole aortas were dissected and photomicrographed. Cross sections of aorta were stained using H&E and EVG. Compared to wild-type, BAPN/AT2 caused dilatation of the aorta from the ascending to the suprarenal segment (p<0.002) with infrarenal sparing (p=0.77). Focal aneurysmal dilatation reproducibly occurred in the suprarenal aorta (wild-type diameter 0.93±0.03mm, n=8; BAPN/AT2 diameter 2.26±0.12, n=8; p<0.0001). Treatment with MK626 attenuated dilatation of the descending aorta compared to controls (BAPN/AT2 control 1.26±0.05mm, n=8; MK626 1.07±0.05mm, n=10; p=0.03). The focal suprarenal aneurysmal dilatation was significantly reduced by treatment with MK626 (BAPN AT2 control 2.26±0.34mm, n=8; MK626 1.66±0.32mm, n=10; p=0.0001). BAPN/AT2 induced aortic aneurysm was associated with excess matrix deposition, increased medial thickness, and elastic fibre fragmentation. Modulation of the GLP pathway using the dipeptidylpeptidase-IV inhibitor MK626 attenuates aneurysm in a BAPN/AT2 induced murine model.