IL-6 regulates extracellular matrix remodeling associated with aortic dilation in a fibrillin-1 hypomorphic mgR/mgR mouse model of severe Marfan syndrome.

Xiaoxi Ju, Talha Ijaz, Hong Sun, Wanda Lejeune, Gracie Vargas, Tuya Shilagard, Adrian Recinos, Dianna M. Milewicz, Allan R. Brasier, Ronald Tilton

Research output: Contribution to journalArticle

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Abstract

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). 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. Activation of IL-6-STAT3 signaling contributes to aneurysmal dilation in mgR/mgR mice through increased MMP-9 activity, aggravating extracellular matrix degradation.

Original languageEnglish (US)
JournalJournal of the American Heart Association
Volume3
Issue number1
DOIs
StatePublished - 2014
Externally publishedYes

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Marfan Syndrome
Extracellular Matrix
Dilatation
Interleukin-6
Elastin
Aortic Aneurysm
Aorta
Collagen
Cytokines
Thoracic Aortic Aneurysm
Aortic Rupture
Adventitia
Matrix Metalloproteinase 9
Granulocyte-Macrophage Colony-Stimulating Factor
Fibrillin-1
Matrix Metalloproteinases
Blood Vessels
Rupture
Microscopy
Inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

IL-6 regulates extracellular matrix remodeling associated with aortic dilation in a fibrillin-1 hypomorphic mgR/mgR mouse model of severe Marfan syndrome. / Ju, Xiaoxi; Ijaz, Talha; Sun, Hong; Lejeune, Wanda; Vargas, Gracie; Shilagard, Tuya; Recinos, Adrian; Milewicz, Dianna M.; Brasier, Allan R.; Tilton, Ronald.

In: Journal of the American Heart Association, Vol. 3, No. 1, 2014.

Research output: Contribution to journalArticle

Ju, Xiaoxi ; Ijaz, Talha ; Sun, Hong ; Lejeune, Wanda ; Vargas, Gracie ; Shilagard, Tuya ; Recinos, Adrian ; Milewicz, Dianna M. ; Brasier, Allan R. ; Tilton, Ronald. / IL-6 regulates extracellular matrix remodeling associated with aortic dilation in a fibrillin-1 hypomorphic mgR/mgR mouse model of severe Marfan syndrome. In: Journal of the American Heart Association. 2014 ; Vol. 3, No. 1.
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abstract = "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). 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. Activation of IL-6-STAT3 signaling contributes to aneurysmal dilation in mgR/mgR mice through increased MMP-9 activity, aggravating extracellular matrix degradation.",
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AU - Lejeune, Wanda

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AU - Recinos, Adrian

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AU - Tilton, Ronald

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