IL-6 regulates extracellular matrix remodeling associated with aortic dilation in a fibrillin-1 hypomorphic mgR/mgR mouse model of severe Marfan syndrome.
BACKGROUND
Development of thoracic aortic aneurysms is the most significant clinical phenotype in patients with Marfan syndrome. An inflammatory response has been described in advanced stages of the disease. Because the hallmark of vascular inflammation is local interleukin-6 (IL-6) secretion, we explored the role of this proinflammatory cytokine in the formation of aortic aneurysms and rupture in hypomorphic fibrillin-deficient mice (mgR/mgR).


RESULTS
MgR/mgR mice developed ascending aortic aneurysms with significant dilation of the ascending aorta by 12 weeks (2.7 ± 0.1 and 1.3 ± 0.1 for mgR/mgR versus wild-type mice, respectively; P<0.001). IL-6 signaling was increased in mgR/mgR aortas measured by increases in IL-6 and SOCS3 mRNA transcripts (P<0.05) and in cytokine secretion of IL-6, MCP-1, and GM-CSF (P<0.05). To investigate the role of IL-6 signaling, we generated mgR homozygous mice with IL-6 deficiency (DKO). The extracellular matrix of mgR/mgR mice showed significant disruption of elastin and the presence of dysregulated collagen deposition in the medial-adventitial border by second harmonic generation multiphoton autofluorescence microscopy. DKO mice exhibited less elastin and collagen degeneration than mgR/mgR mice, which was associated with decreased activity of matrix metalloproteinase-9 and had significantly reduced aortic dilation (1.0 ± 0.1 versus 1.6 ± 0.2 mm change from baseline, DKO versus mgR/mgR, P<0.05) that did not affect rupture and survival.


CONCLUSIONS
Activation of IL-6-STAT3 signaling contributes to aneurysmal dilation in mgR/mgR mice through increased MMP-9 activity, aggravating extracellular matrix degradation.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX.
Xiaoxi
X
Ju
Talha
T
Ijaz
Hong
H
Sun
Wanda
W
Lejeune
Gracie
G
Vargas
Tuya
T
Shilagard
Adrian
A
Recinos
Dianna M
DM
Milewicz
Allan R
AR
Brasier
Ronald G
RG
Tilton
D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D001019:Aortic Rupture / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D000071838:Fibrillin-1; D000071837:Fibrillins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008382:Marfan Syndrome / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D054392:Adipokines
D018932:Chemokine CCL2; D003094:Collagen; D004549:Elastin; D000071838:Fibrillin-1; D000071837:Fibrillins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015850:Interleukin-6; D020780:Matrix Metalloproteinase 9; D008840:Microfilament Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C491768:Ccl2 protein, mouse; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; C577686:interleukin-6, mouse; C501830:Mmp9 protein, mouse
Marfan syndrome; extracellular matrix; interleukin‐6; matrix metalloproteinases; mgR; thoracic aortic aneurysms and dissections; vascular inflammation