Abstract 12514: Deletion of Angiotensin IV Receptor (AT4R) Promotes Inflammation and Accelerates Development of Angiotensin II-Induced Aortic Aneurysms
Insulin-regulated aminopeptidase (IRAP) has been identified a key regulator of MHC class I cross-presentation as well as angiotensin IV (AngIV) receptor (AT4R). We hypothesized that IRAP contributes to arterial inflammation and aortic wall degradation in the process of abdominal aortic aneurysm (AAA) formation. We evaluated the pathophysiological changes in the aorta of ApoE-null (ApoE−/−) and ApoE/IRAP-null (DKO) mice after AngII infusion.
[Methods and Results] [in vitro] In cultured vascular smooth muscle cells (VSMC) explanted from murine aorta, IRAP protein levels were elevated in ApoE−/− (C57BL6/J strain) after AngII treatment (10−6 M for 24h), while both AT1R and AT2R levels were elevated only in DKO (2.5- and 3.8-fold, respectively, P<0.01 each). Although apoptosis rate (ELISA for DNA fragmentation) was higher in DKO than ApoE−/− (1.28±0.11 vs. 1.83±0.14 a.u., mean ±SD, P=0.032), VSMC migration was accelerated in DKO after PDGF-BB treatment (10 ng/ml) if compared with ApoE−/−. [in vivo] Mice fed normal chow were infused with AngII (1.4 mg/kg/day) for 4 weeks (n=15 each). AngII infusion significantly elevated blood pressure in either mice with a similar degree (ApoE−/− : DKO = 92±9.0 to 148±12 : 96±9.2 to 145±14 mmHg), but did not alter lipid metabolism between 2 groups. AngII-induced AAA formation was frequently observed in DKO if compared to ApoE−/− (87% vs. 33%) with a concordant increase of reactive oxygen metabolites in the plasma (ApoE−/− : DKO = 78±7.6 to 85±10 : 82±7.8 to 112±14* a.u., *P=0.028). Gelatin zymography demonstrated that IRAP deletion increased MMP-9 activity in the aortic wall. DKO mice showed increased levels of monocyte chemoattractant protein-1 and NFκB activation (phosphorylated IκB-α) in the aorta with greater degrees of elastic lamina degradation (“medial break”; 1.02 vs. 0.38 /aorta), intraplaque hemorrhage (0.58 vs. 0.12 /aorta), microvessel formation (3.26±0.24 vs. 2.17±0.15 /area, P=0.0034), and aortic expansion (average diameter at the suprarenal aorta; 2.02±0.16 vs. 1.56±0.13 mm, P=0.011).
[Conclusions] In an AngII-induced AAA model, IRAP/AT4R deletion increases incidence and severity of aneurysms by promoting proinflammatory cytokine expression, leukocyte infiltration, and metalloprotease activity.
- © 2010 by American Heart Association, Inc.