Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by local connective tissue degradation, macrophage recruitment and infiltration leading to aortic dilation and rupture. Aneurysms of the abdominal aorta represent a significant cardiovascular risk for which inflammation plays an integral role in the defined pathology. Genetic ablation of metalloprotease-12 (MMP-12) eliminates metalloelastase activity and attenuates aneurysm formation in apoE−/− mice. In the current study, a selective MMP-12 inhibitor, WAY-644 was evaluated in the well-established murine model of ANGII-induced aneurysm formation. This inhibitor displays activity for murine MMP-12, IC50 = 6.3 nM by FRET analysis, with low crossreactivity for other MMPs (exception MMP-8), and has established
in vivo
efficacy in inflammation models. Coadministration of WAY-644 to hyperlipidemic apoE−/− mice during ANGII infusion (1.44 mg/kg) for 28d alters the severity of AngII-induced AAAs as measured by changes in abdominal aortic wet weights and typical AAA classification. As expected, plasma MMP-12 protease activity measured by FRET analysis was inhibited. RNA profiling of abdominal aortic aneurysm tissue characterizes ANGII-induced AAA expansion driven by macrophage infiltration, destructive MMP production and attenuation by MMP-12 inhibition. The transcription of a subset of proinflammatory genes activated with ANGII treatment was repressed by the inhibitor. These genes include quantitative markers of macrophage accumulation in the vessel wall, CD68, MCP1/CCL2, CCR2, MMP-12, and Csf1. Associated reductions in gene markers for inflammation and oxidative stress, ie., heme oxidase (HO), nitric oxide synthase (nos2), Ikbkb, and Stat3 also correlate with MMP-12 antagonism. These changes occur in the absence of lipid changes (TC or TG), or quantitative changes in aortic arch lesions in the ANGII-infused animals. The findings support a mechanism whereby MMP-12 metalloelastase inactivation reduces macrophage recruitment to aneurysmal lesion sites, to lessen activated-macrophage expression of proinflammatory cytokines that figure prominently in vascular wall destruction and the pathogenesis of AAAs.
Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo
