Abstract 13212: The Role of Macrophage STAT3 Signaling in Pathogenesis of Aortic Dissection
Aortic dissection (AD) is a fatal disease caused by the disruption of the intimomedial layer. Recent studies showed that IL-6, a STAT3-activating cytokine, and macrophages play important roles in AD. However, it is unknown whether or how activation of macrophage STAT3 is involved in AD pathogenesis. To answer this question, we examined both mouse AD model and human AD tissue. We used macrophage-specific knockout of SOCS3 (mSOCS3-KO), a negative regulator of STAT3, to specifically sensitize macrophages to STAT3 activation, and compared them with wild type (WT) mice. We created a mouse model of aortic stiffening by periaortic CaCl2 treatment of abdominal aorta, and infused them with angiotensin II (Ca+AngII), which augmented hemodynamic stress to aortic walls. Both WT and mSOCS3-KO showed microscopic injuries in aorta with equal frequencies (40%) 1 week after Ca+AngII. Whereas WT showed fibrotic repair of the injury, mSOCS3-KO failed to show such reparative response and developed large AD in 6 weeks. We analyzed the aorta 1 week after the Ca+AngII stimulation, focusing on the changes in aorta preceding AD development. Transcriptome analysis showed higher activation of cell cycle followed by higher proinflammatory response in mSOCS3-KO than in WT aorta before AD development. Ki67 staining and BrdU uptake study confirmed the proliferative response of inflammatory cells in aorta. Flowcytometric analysis showed preferential differentiation of mSOCS3-KO macrophages to proinflammatory M1 with reduction in reparative M2 population (M1:M2 = 2:1), while WT macrophages differentiated equally to M1 and M2. Immunofluorescence study of human AD tissue showed the infiltration of CD68-positive macrophages in adventitia and outer media at the site of dissection and surrounding intact aortic walls. The infiltrating cells showed high phospho- (active) STAT3 and Ki67. Interestingly, STAT3 was less active in tissue with fibrotic changes, suggesting the negative association of STAT3 activation and tissue repair. Therefore, macrophage STAT3 activation resulted in higher proliferation and M1 differentiation, which is likely to promote AD development. Over activation of STAT3 in macrophages may be a therapeutic target to mitigate the destructive process in AD.
Author Disclosures: S. Ohno: None. H. Aoki: None. M. Nishihara: None. A. Furusho: None. S. Hirakata: None. N. Nishida: None. S. Ito: None. M. Hayashi: None. Y. Fukumoto: None.
- © 2015 by American Heart Association, Inc.