Abstract
Bicuspid aortic valve (BAV) disease is recognized to be a syndrome with a complex and multifaceted pathophysiology. Its progression is modulated by diverse evolutionary conserved pathways, such as Notch-1 pathway. Emerging evidence is also highlighting the key role of TLR4 signaling pathway in the aortic valve pathologies and their related complications, such as sporadic ascending aorta aneurysms (AAA). Consistent with these observations, we aimed to evaluate the role of TLR4 pathway in both BAV disease and its common complication, such as AAA. To this aim, 70 subjects with BAV (M/F 50/20; mean age: 58.8 ± 14.8 years) and 70 subjects with tricuspid aortic valve (TAV) (M/F 35/35; mean age: 69.1 ± 12.8 years), with and without AAA were enrolled. Plasma assessment, tissue and gene expression evaluations were performed. Consistent with data obtained in the previous study on immune clonotypic T and B altered responses, we found reduced levels of systemic TNF-α, IL-1, IL-6, IL-17 cytokines in BAV cases, either in the presence or absence of AAA, than TAV cases (p < 0.0001 by ANOVA test). Interestingly, we also detected reduced levels of s-TLR4 in BAV cases with or without AAA in comparison to the two groups of TAV subjects (p < 0.0001 by ANOVA test). These results may suggest a deregulation in the activity or in the expression of TLR4 signaling pathway in all BAV cases. Portrait of these data is, indeed, the significantly decreased gene expression of inflammatory cytokines and TLR4, in both normal and aneurysmatic tissue samples, from BAV with AAA than TAV with AAA. In conclusion, our study demonstrates that subjects with BAV display a significant deregulation of TLR4 signaling pathway paralleled by a deregulation of Notch-1 pathway, as previously showed. This data suggests that the crosstalk between the Notch-1 and TLR4 signaling pathways may play a crucial role in both physiological embryological development, and homeostasis and functionality of aortic valve in adult life.
Highlights
A novel evidence sustains that the Toll-like receptor-4 (TLR4) signaling pathway has the role of hub in preserving aorta homeostasis, and in contributing to the onset of degenerative aorta diseases, such as aneurysms[1]
We investigated if TLR4 signaling pathway is involved as one of the main determinants of both pathophysiology and early onset of ascending aortic aneurysms (AAA) in patients affected by bicuspid aortic valve (BAV)
In BAV subjects with AAA, we observed a significant increase of systemic levels of these cytokines when compared to the levels of BAV cases without AAA
Summary
A novel evidence sustains that the Toll-like receptor-4 (TLR4) signaling pathway has the role of hub in preserving aorta homeostasis, and in contributing to the onset of degenerative aorta diseases, such as aneurysms[1] Consistent with this, it is emerging the key role of TLR4 signaling pathway in the complex pathophysiology of sporadic ascending aortic aneurysms (AAA)[1]. A growing evidence supports these observations, as reported in previous works[1,16] Alterations in these pathways result in a deregulation of vascular homeostasis and valvulogenesis, followed by both valve and vascular structure abnormalities and the onset of pathological conditions, such as valve degeneration, endothelial dysfunction, medial degeneration and vascular degeneration, significantly associated with the development and progression of AAA. The main aim was to evaluate TLR-4 signaling in a cohort of BAV and TAV patients, with or without AAA13
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