Transforming growth factor-β and inflammation in vascular (type IV) Ehlers-Danlos syndrome.

Morissette, Rachel; Schönhoff, Florian; Xu, Zhi; Shilane, David A; Griswold, Benjamin F; Chen, Wuyan; Yang, Jiandong; Zhu, Jie; Fert-Bober, Justyna; Sloper, Leslie; Lehman, Jason; Commins, Natalie; Van Eyk, Jennifer E; McDonnell, Nazli B (2014). Transforming growth factor-β and inflammation in vascular (type IV) Ehlers-Danlos syndrome. Circulation - cardiovascular genetics, 7(1), pp. 80-88. Lippincott Williams & Wilkins 10.1161/CIRCGENETICS.113.000280

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BACKGROUND Vascular Ehlers-Danlos syndrome (VEDS) causes reduced life expectancy because of arterial dissections/rupture and hollow organ rupture. Although the causative gene, COL3A1, was identified >20 years ago, there has been limited progress in understanding the disease mechanisms or identifying treatments. METHODS AND RESULTS We studied inflammatory and transforming growth factor-β (TGF-β) signaling biomarkers in plasma and from dermal fibroblasts from patients with VEDS. Analyses were done in terms of clinical disease severity, genotype-phenotype correlations, and body composition and fat deposition alterations. VEDS subjects had increased circulating TGF-β1, TGF-β2, monocyte chemotactic protein-1, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and leptin and decreased interleukin-8 versus controls. VEDS dermal fibroblasts secreted more TGF-β2, whereas downstream canonical/noncanonical TGF-β signaling was not different. Patients with COL3A1 exon skipping mutations had higher plasma intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and VEDS probands had abnormally high plasma C-reactive protein versus affected patients identified through family members before any disease manifestations. Patients with VEDS had higher mean platelet volumes, suggesting increased platelet turnover because of ongoing vascular damage, as well as increased regional truncal adiposity. CONCLUSIONS These findings suggest that VEDS is a systemic disease with a major inflammatory component. C-reactive protein is linked to disease state and may be a disease activity marker. No changes in downstream TGF-β signaling and increased platelet turnover suggest that chronic vascular damage may partially explain increased plasma TGF-β1. Finally, we found a novel role for dysregulated TGF-β2, as well as adipocyte dysfunction, as demonstrated through reduced interleukin-8 and elevated leptin in VEDS.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiovascular Surgery

UniBE Contributor:

Schönhoff, Florian

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1942-325X

Publisher:

Lippincott Williams & Wilkins

Language:

English

Submitter:

Sara Baumberger

Date Deposited:

20 Feb 2015 14:37

Last Modified:

27 Oct 2015 11:29

Publisher DOI:

10.1161/CIRCGENETICS.113.000280

PubMed ID:

24399159

Uncontrolled Keywords:

Ehlers-Danlos syndrome, aneurysm, biomarkers, extracellular matrix, inflammation

BORIS DOI:

10.7892/boris.63384

URI:

https://boris.unibe.ch/id/eprint/63384

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