A gm-csf negative modulator for use in treating, preventing or ameliorating aortopathy
A technology of GM-CSF and negative regulators, which is applied in the fields of disease diagnosis, antibody medical components, and cardiovascular system diseases, and can solve the problems of lack of animal models and unclear basic mechanisms
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Embodiment 1
[0137] Example 1: Aortic aneurysm with inflammation in KLF6 heterozygous knockout mice
[0138] The inventors of the present application initially found that mice depleted of KLF6 in a heterozygous manner were significantly more susceptible to aortic inflammation [after topical application of calcium chloride (CaCl 2 ) showed an aortic exacerbation phenotype (defined as greater than 50% increase in external aortic diameter with preservation of the aortic wall) (21,22) . Histological findings showed dilation of the aortic lumen with fragility of the aortic wall and further fibrotic tissue deposition with marked infiltration of macrophages (Mac3-positive cells) ( figure 1 a-e). Mechanistically, matrix metalloproteinase-9 (MMP9, as a marker of vascular remodeling) (23), F4 / 80 (as a marker of macrophages) (24,25) and IL- 6 (as a marker of inflammation) (16,26-30) increased expression ( figure 1 f).
[0139] Since a marked infiltration of immune cells was seen in the disea...
Embodiment 2
[0140] Example 2: KLF6fl / fl; LysMCre mice exhibit aortic dissection / hematoma
[0141] Since the aortic condition in KLF6-deficient mice appears to involve a dysregulated inflammatory response of macrophages, bone marrow-specific KLF6-deficient mice (KLF6fl / fl; LysM Cre mice) were further generated, which exhibited 70% specific reduction in KLF6 expression compared to myeloid lineage. KLF6fl / fl;LysM Cre mice subjected to aortic inflammation displayed a phenotype of abdominal aortic aneurysm exacerbation similar to that seen in heterozygous knockout mice, but interestingly also showed renal Superior aortic dissection / intramural hematoma, which is defined as separation of the inner wall of the aorta and hematoma formation and for dissection with intimal tear(3)( Figure 6 ). The lesion also showed fibrotic tissue deposition with infiltration of Mac3-positive macrophages ( figure 2 b-e and Figure 7 a, b), thus confirming that the aortic phenotype in KLF6 deficiency is asso...
Embodiment 3
[0144] Example 3: GM-CSF is a downstream target of KLF6
[0145]RNA profiling array analysis was subsequently used to address the delineation of target molecules and regulatory mechanisms of immune cells. Notably, GM-CSF levels in macrophages derived from the bone marrow of KLF6fl / fl;LysM Cre mice showed the greatest increase (3.89-fold) in response to AngII stimulation compared to control macrophages ( image 3 a).
[0146] Surprisingly, in CaCl 2 Macrophages obtained from the aorta of KLF6fl / fl;LysM Cre mice under the experimental conditions of administration and AngII infusion showed a significant increase in the expression of GM-CSF ( image 3 b), and also in macrophages derived from the bone marrow of these mice ( Figure 10 a). The expression of GM-CSF in the aorta of KLF6fl / fl;LysM Cre mice increased from three days after treatment (before the onset of aortic dissection) ( image 3 c). It was subsequently investigated whether loss of KLF6 in macrophages affected GM...
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