Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma

• Published in: Nature communications 2015-04, Vol.6 (1), p.6994-6994, Article 6994
• Main Authors: Son, Bo-Kyung, Sawaki, Daigo, Tomida, Shota, Fujita, Daishi, Aizawa, Kenichi, Aoki, Hiroki, Akishita, Masahiro, Manabe, Ichiro, Komuro, Issei, Friedman, Scott L., Nagai, Ryozo, Suzuki, Toru
• Format: Article
• Language: English
• Subjects: 631/45/612/1231; 692/1807; 692/420/256; 692/699/75; Adult; Aged; Aged, 80 and over; Aneurysm, Dissecting - blood; Aneurysm, Dissecting - etiology; Animals; Aortic Aneurysm - blood; Aortic Aneurysm - etiology; Case-Control Studies; Female; Granulocyte-Macrophage Colony-Stimulating Factor - blood; Hematoma - blood; Hematoma - etiology; Humanities and Social Sciences; Humans; Kruppel-Like Factor 6; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; multidisciplinary; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Science; Science (multidisciplinary); Up-Regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7994

Aortic dissection and intramural haematoma comprise an aortopathy involving separation of the aortic wall. Underlying mechanisms of the condition remain unclear. Here we show that granulocyte macrophage colony-stimulating factor (GM-CSF) is a triggering molecule for this condition. Transcription factor Krüppel-like factor 6 (KLF6)-myeloid-specific conditional deficient mice exhibit this aortic phenotype when subjected to aortic inflammation. Mechanistically, KLF6 downregulates expression and secretion of GM-CSF. Administration of neutralizing antibody against GM-CSF prevents the condition in these mice. Conversely, administration of GM-CSF in combination with aortic inflammation to wild-type mice is sufficient to induce the phenotype, suggesting the general nature of effects. Moreover, patients with this condition show highly increased circulating levels of GM-CSF, which is also locally expressed in the dissected aorta. GM-CSF is therefore a key regulatory molecule causative of this aortopathy, and modulation of this cytokine might be an exploitable treatment strategy for the condition. Aortic dissection and intramural haematoma are caused by separation of the aortic wall via an unknown mechanism. Here the authors show that the inflammatory cytokine, granulocyte macrophage colony-stimulating factor, is a central regulatory molecule causative of these conditions in mice and humans.