SMAD3 contributes to ascending aortic dilatation independent of transforming growth factor-beta in bicuspid and unicuspid aortic valve disease

Abstract

We sought to determine whether there are differences in transforming growth factor-beta (TGFß) signaling in aneurysms associated with bicuspid (BAV) and unicuspid (UAV) aortic valves versus normal aortic valves. Ascending aortic aneurysms are frequently associated with BAV and UAV. The mechanisms are not yet clearly defined, but similarities to transforming growth factor-beta TGFß vasculopathies (i.e. Marfan, Loeys-Dietz syndromes) are reported. Non-dilated (ND) and aneurysmal (D) ascending aortic tissue was collected intra-operatively from individuals with a TAV (N = 10ND, 10D), BAV (N = 7ND, 8D) or UAV (N = 7ND, 8D). TGFß signaling and aortic remodeling were assessed through immuno-assays and histological analyses. TGFß1 was increased in BAV/UAV-ND aortas versus TAV (P = 0.02 and 0.04, respectively). Interestingly, TGFß1 increased with dilatation in TAV (P = 0.03) and decreased in BAV/UAV (P = 0.001). In TAV, SMAD2 and SMAD3 phosphorylation (pSMAD2, pSMAD3) increased with dilatation (all P = 0.04) and with TGFß1 concentration (P = 0.04 and 0.03). No relationship between TGFß1 and pSMAD2 or pSMAD3 was observed for BAV/UAV (all P > 0.05). pSMAD3 increased with dilatation in BAV/UAV aortas (P = 0.01), whereas no relationship with pSMAD2 was observed (P = 0.56). Elastin breaks increased with dilatation in all groups (all P < 0.05). In TAV, elastin degradation correlated with TGFß1, pSMAD2 and pSMAD3 (all P < 0.05), whereas in BAV and UAV aortas, elastin degradation correlated only with pSMAD3 (P = 0.0007). TGFß signaling through SMAD2/SMAD3 contributes to aortic remodeling in TAV, whereas TGFß-independent activation of SMAD3 may underlie aneurysm formation in BAV/UAV aortas. Therefore, SMAD3 should be further investigated as a therapeutic target against ascending aortic dilatation in general, and particularly in BAV/UAV patients.

Epigenome-Wide Changes in the Cell Layers of the Vein Wall When Exposing the Venous Endothelium to Oscillatory Shear Stress

“…It is known that rs17684886 in ZNRF1 is associated with diabetic retinopathy [ 81 ], and its expression is induced in peripheral nerves after injury [ 82 ], so its overexpression causes neurite-like elongation. It has been found that expression of the SMAD2 protein is progressively increased in reactive lesions and oral submucous fibrosis (OSMF) [ 83 ], and SMAD3 contributes to ascending aortic dilatation independently of transforming growth factor-beta in bicuspid and unicuspid aortic valve disease [ 84 ], which is consistent with our data.…”

Can transforming growth factor beta and downstream signalers distinguish bicuspid aortic valve patients susceptible for future aortic complications?

“…Studies focusing on the TGF-β signaling pathway in BAV patients on tissue level found a decreased expression of TGF-β and the downstream signalers phosphorylated SMAD2 (pSMAD2) and SMAD3 (pSMAD3) in the non-and dilated aorta of BAV patients [8][9][10] ( Table 1 ). Recently, Balint et al also found that in the dilated aorta of BAV patients the expression of TGFß1 is significantly lower as compared to the dilated TAV patients [11] . Interestingly, the authors described that in BAV patients the pSMAD2/pSMAD3 and TGFß1 expressions were not correlated [11] ( Table 1 previous study, we reported a non-homogenous expression pattern of TGF-ß in the aortic wall.…”

“…Recently, Balint et al also found that in the dilated aorta of BAV patients the expression of TGFß1 is significantly lower as compared to the dilated TAV patients [11] . Interestingly, the authors described that in BAV patients the pSMAD2/pSMAD3 and TGFß1 expressions were not correlated [11] ( Table 1 previous study, we reported a non-homogenous expression pattern of TGF-ß in the aortic wall. We found that TGF-ß is mainly expressed in the outer media and that the inner and middle media are completely devoid of TGFß.…”

The role of transforming growth factor beta in bicuspid aortic valve aortopathy

“…Medial accumulation of mucoid extracellular matrix components is significantly higher in non-dilated and dilated BAV patients as compared to the TAV (Fig. 4 D) [ 37 , 59 ].…”