Deregulation of TLR4 signaling pathway characterizes Bicuspid Aortic valve syndrome

• Published in: Scientific reports Vol. 9; no. 1; pp. 11028 - 8
• Main Authors: Balistreri, Carmela R., Marullo, Antonino G. M., Madonna, Michele, Cavarretta, Elena, Allegra, Alberto, Cesarini, Valeriana, Iaccarino, Alessandra, Schiavon, Sonia, Peruzzi, Mariangela, Greco, Ernesto, Sciarretta, Sebastiano, Pisano, Calogera, Ruvolo, Giovanni, Torella, Michele, Frati, Giacomo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.07.2019; Nature Publishing Group
• Subjects: 38; 692/4019; 692/4019/592/75/591; Aged; Aged, 80 and over; Aorta; Aorta - metabolism; Aortic valve; Aortic Valve - abnormalities; Aortic Valve - metabolism; Bicuspid Aortic Valve Disease; Cytokines; Deregulation; Evolutionary conservation; Female; Gene expression; Heart Valve Diseases - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Inflammation; Interleukin 1; Interleukin 17; Interleukin 6; Interleukins - blood; Interleukins - genetics; Interleukins - metabolism; Male; Middle Aged; multidisciplinary; Notch1 protein; Science; Science (multidisciplinary); Signal Transduction; Syndrome; TLR4 protein; Toll-Like Receptor 4 - blood; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; Variance analysis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-47412-0

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.