Atsushi Anzai1, Masayuki Shimoda1, Jin Endo1, Takashi Kohno1, Yoshinori Katsumata1, Tomohiro Matsuhashi1, Tsunehisa Yamamoto1, Kentaro Ito1, Xiaoxiang Yan1, Kosuke Shirakawa1, Ryoko Shimizu-Hirota1, Yoshitake Yamada1, Satoshi Ueha1, Ken Shinmura1, Yasunori Okada1, Keiichi Fukuda1, Motoaki Sano2. 1. From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.). 2. From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.). msano@a8.keio.jp.
Abstract
RATIONALE: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. OBJECTIVE: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. METHODS AND RESULTS: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. CONCLUSIONS: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.
RATIONALE: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. OBJECTIVE: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. METHODS AND RESULTS: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. CONCLUSIONS: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.
Authors: Dong-chuan Guo; Ellen S Regalado; Limin Gong; Xueyan Duan; Regie Lyn P Santos-Cortez; Pauline Arnaud; Zhao Ren; Bo Cai; Ellen M Hostetler; Rocio Moran; David Liang; Anthony Estrera; Hazim J Safi; Suzanne M Leal; Michael J Bamshad; Jay Shendure; Deborah A Nickerson; Guillaume Jondeau; Catherine Boileau; Dianna M Milewicz Journal: Circ Res Date: 2016-01-12 Impact factor: 17.367