Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture

Atsushi Anzai, Masayuki Shimoda, Jin Endo, Takashi Kono, Yoshinori Katsumata, Tomohiro Matsuhashi, Tsunehisa Yamamoto, Kentaro Ito, Xiaoxiang Yan, Kosuke Shirakawa, Ryoko Shimizu-Hirota, Yoshitake Yamada, Satoshi Ueha, Ken Shinmura, Yasunori Okada, Keiichi Fukuda, Motoaki Sano

Research output: Contribution to journalArticle

57 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)612-623
Number of pages12
JournalCirculation research
Volume116
Issue number4
DOIs
Publication statusPublished - 2015 Feb 13

Keywords

  • Angiotensin II
  • Aortic dissection
  • Chemokines
  • Inflammation
  • Interleukin-6
  • Neutrophils

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture'. Together they form a unique fingerprint.

  • Cite this