Backgound:
The Receptor for Advanced Glycation End products (RAGE) and its ligands are associated with vascular remodeling and trigger the release of a soluble receptor (sRAGE). We demonstrated that sRAGE is elevated in patients with thoracic aortic disease such as patients with bicuspid aortic valve and Marfan syndromes. Circulating sRAGE in these patients correlates with the presence of a dysfunctional aortic structure without linearly correlating with increasing aortic diameter. We hypothesized that elevated sRAGE levels are the result of structural degeneration during aortic aneurysm formation and that they are affected by pharmacological treatments aimed to inhibit vascular remodeling.
Methods:
Circulating sRAGE was tested by ELISA in two mouse models of thoracic aortic aneurysm (TAA): the AngII chronic infusion model and the hypomorphic FBN1
mgR/mgR
. C57BL6 mice were treated with AngII via osmotic pump for 28 days with or without losartan in drinking water. FBN1
mgR/mgR
mice were treated with losartan starting from postnatal day 16 (p16). Ascending aorta and blood were collected at day 28 of AngII infusion or at p60 in the hypomorphic model. Aortic dilatation and degeneration were tested by echocardiography and histological analysis.
Results:
Plasma sRAGE is significantly higher in AngII treated animals when compared to controls (118.1± 8.3 vs 45.6±5.01 pg/ml,
p
<0.0001) and is associated with aortic aneurysm formation and increased medial thickening. Similarly, sRAGE levels are higher in FBN1
mgR/mgR
mice compared to age-matched wild type (1939 ± 320.5 vs 45.6±5.01 pg/ml,
p
<0.0001) in concomitance with elastin degradation (media score 3.5± 0.8 vs 1.03.5± 0.2,
p
<0.05) and proximal aorta enlargement. Plasma sRAGE decreases in AngII and FBN1
mgR/mgR
mice treated with losartan when compared to age matched untreated or wild type mice (73±24.5 vs 118.1 ± 8.296 pg/ml, p<0.05 and 260.7 ± 4.333 vs 1939 ± 320.5 pg/ml, p<0.001) together with reduced aorta dilatation, medial thickening and elastin fragmentation.
Conclusion:
sRAGE is elevated in the presence of aortic dilatation in mouse models of TAA, as seen in human aneurysmal patients. These results suggest that sRAGE may be used as a circulating biomarker to assess disease severity in patients with TAA.
Rapamycin inhibits CaCl2-induced thoracic aortic aneurysm formation in rats through mTOR-mediated suppression of proinflammatory mediators
