Inflammation Aggravates Disease Severity in Marfan Syndrome Patients

Abstract

BackgroundMarfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far.Methodology/Principal FindingsHere we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10−6, 95% CI: 70–159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.Conclusion/SignificanceIn conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

Circulating Transforming Growth Factor <I>&beta;</I>-1 Level in Japanese Patients With Marfan Syndrome

“…In contrast, Radonic, et al 11) reported very low levels of plasma TGFβ1, which were 124 pg/mL for MFS patients with aortic dilatation and 10 pg/mL for MFS patients with normal aorta using ELISA, and showed large discrepancies from the above studies. Further studies are needed to defi ne the optimal method for plasma TGFβ1 measurement.…”

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

“…19) In addition, inflammatory T lymphocytes and macrophages reportedly infiltrate aortic media and adventitia, and those numbers were negatively correlated with patient ages at referral for prophylactic surgical repair, suggesting that inflammation might affect disease progression. 20,21) Dietz and his colleagues performed the most extensive mechanistic studies of these diseases, and identified FBN1 as a causative gene in 1991, 4) with FBN1 mutations accounting for > 60% of MFS patients. FBN1 is a 230 kb gene with 65 exons, and the encoded microfibrillar protein fibrillin-1 contains 7 TGF-β binding protein-like (TB) domains and 47 epidermal growth factor (EGF)-like domains, which are characterized by 8 and 6 conserved cysteine residues that form 4 and 3 intramodule disulfide bonds, respectively.…”

“…Accordingly, treatment with a miR-29b oligonucleotide inhibitor prevented early formation of aneurysms. 41) Finally, plasma levels of TGF-β, 26) fibrillin-1 fragments, 42) macrophage colony stimulating factor (M-CSF), 21) and oxidative stress indicators 43) have been reported as useful biomarkers for disease progression in humans and animal models. C1039G/+ mice showed significant increases in activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated protein kinase kinase 1 (MEK1), which is the upstream activator of ERK1/2.…”

Molecular pathogenesis of Marfan syndrome

“…Loss of fibrillin-1 releases TGF-β and its constitutive stimulation activates genes like MMPs which induce elastolysis, decreasing ECM stability. and adventitia respectively [65]. Furthermore, the interleukin-6/STAT3 signaling pathway was recently implicated in aortic dilation through increased MMP-9 activity in MFS mice [66].…”