Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma.
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.
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
Bo-Kyung
BK
Son
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
Daigo
D
Sawaki
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
Shota
S
Tomida
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
Daishi
D
Fujita
1] Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan [2] Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken 329-0498, Japan.
Kenichi
K
Aizawa
Cardiovascular Research Institute, Kurume University, 67 Asahi-machi Kurume-shi, Fukuoka-ken 830-0011, Japan.
Hiroki
H
Aoki
Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
Masahiro
M
Akishita
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
Ichiro
I
Manabe
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
Issei
I
Komuro
Division of Liver Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1428 Madison Avenue, New York, New York 10029, USA.
Scott L
SL
Friedman
Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken 329-0498, Japan.
Ryozo
R
Nagai
1] Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan [2] Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken 329-0498, Japan [3] Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK [4] National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Groby Road, Glenfield, Leicester LE3 9QP, UK.
Toru
T
Suzuki
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000784:Aortic Dissection / Q000097:blood / Q000209:etiology*; D000818:Animals; D001014:Aortic Aneurysm / Q000097:blood / Q000209:etiology*; D016022:Case-Control Studies; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood*; D006406:Hematoma / Q000097:blood / Q000209:etiology*; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor