Abstract 12671: Deciphering the Sequential Molecular Events During Onset of Acute Aortic Dissection
Acute aortic dissection (AAD) is a common disease with sudden onset, caused by the partial rupture of the intimomedial layer and tearing of the aortic walls, and with high mortality. Currently, effective medical therapy for AAD is not available because molecular pathogenesis of AAD is largely unknown. Previously we reported that stiffening of aortic walls by periaortic application of CaCl2 augmented the aortic stress by angiotensin II (Ca+AngII), which resulted in AAD development in 6 weeks in tenascin C-deficient mice due to impaired tissue healing.
In this study, we first examined wild type mice (WT) 1 week after Ca+AngII and found microscopic medial injury in 40% of mice, which healed with fibrosis in 6 weeks. Because infiltrating macrophages exhibited STAT3 activation 1 week after Ca+AngII, we investigated its significance by using macrophage-specific knockout of SOCS3, a negative regulator of STAT3 signaling (mSOCS3-KO). Both WT and mSOCS3-KO showed equivalent extent of microscopic medial injury with 40% of frequencies 1 week after Ca+AngII, indicating that macrophage STAT3 pathway does not play a major role up to this stage. However, 25% mSOCS3-KO developed marked enlargement of the suprarenal aorta 6 weeks after Ca+AngII, while only 8% of WT showed such a phenotype. Histological analysis showed the rupture of the intimomedial layer, intramural hematoma and the double-barrel appearance of true and false lumens, hallmarks of AAD, in the enlarged aorta. Stage-specific transcriptome analysis showed the enhanced expression of cell cycle genes, followed by the activation of inflammatory genes in mSOCS3-KO compared to WT before the onset of AAD. Flow cytometric analysis revealed the proinflammatory M1-skewed differentiation of mSOCS3-KO macrophages compared to WT in the aorta with microscopic injury.
These results suggest that activation of macrophage STAT3 signaling resulted in the expansion of inflammatory cells and M1 polarization of macrophages at the stage of microscopic medial injury, which lead to the development of AAD. Deciphering such sequential molecular events during the development of AAD will be essential to develop a new diagnostic and therapeutic strategies for this lethal disease.
- © 2013 by American Heart Association, Inc.