Abstract
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.
Highlights
Aortic dissection and intramural haematoma comprise an aortopathy involving separation of the aortic wall
We hypothesized that this factor might regulate pathogenic mechanisms underlying aortic disease, and observed that mice deficient for Kruppel-like factor 6 (KLF6) in macrophages when subjected to aortic inflammation manifest aortic dissection/intramural haematoma
We initially found that mice heterozygously depleted for Klf[6] manifest a phenotype of exacerbated aortic aneurysm[21,22], when subjected to aortic inflammation (2 weeks infusion of angiotensin II (AngII) with local application of calcium chloride (CaCl2))
Summary
Aortic dissection and intramural haematoma comprise an aortopathy involving separation of the aortic wall. 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. Patients with this condition show highly increased circulating levels of GM-CSF, which is locally expressed in the dissected aorta. We hypothesized that this factor might regulate pathogenic mechanisms underlying aortic disease, and observed that mice deficient for KLF6 in macrophages when subjected to aortic inflammation manifest aortic dissection/intramural haematoma. Administration of the cytokine in combination with aortic inflammation to wild-type mice is sufficient to induce the condition, suggesting general effects. GM-CSF is a key regulatory molecule causative of aortic dissection/intramural haematoma
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