Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, Palermo, Italy.
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
Sci Rep. 2019 Jul 30;9(1):11028. 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.
二叶式主动脉瓣（BAV）疾病被认为是一种具有复杂和多方面病理生理学的综合征。其进展受到多种进化保守途径的调节，如 Notch-1 途径。新出现的证据也强调了 TLR4 信号通路在主动脉瓣病变及其相关并发症（如散发性升主动脉瘤（AAA））中的关键作用。与这些观察结果一致，我们旨在评估 TLR4 通路在 BAV 疾病及其常见并发症（如 AAA）中的作用。为此，我们招募了 70 名 BAV 患者（M/F 50/20；平均年龄：58.8±14.8 岁）和 70 名三叶式主动脉瓣（TAV）患者（M/F 35/35；平均年龄：69.1±12.8 岁），包括有和没有 AAA 的患者。进行了血浆评估、组织和基因表达评估。与之前关于免疫克隆型 T 和 B 改变反应的研究数据一致，我们发现 BAV 病例（无论是否存在 AAA）的全身 TNF-α、IL-1、IL-6、IL-17 细胞因子水平均低于 TAV 病例（方差分析检验，p<0.0001）。有趣的是，我们还发现，与两组 TAV 患者相比，有或没有 AAA 的 BAV 患者的 s-TLR4 水平也较低（方差分析检验，p<0.0001）。这些结果可能表明，在所有 BAV 病例中，TLR4 信号通路的活性或表达受到了调节。事实上，与 TAV 伴 AAA 相比，BAV 伴 AAA 的正常和动脉瘤组织样本中炎症细胞因子和 TLR4 的基因表达均显著降低。总之，我们的研究表明，BAV 患者的 TLR4 信号通路存在显著失调，如前所述，Notch-1 通路也存在失调。这些数据表明，Notch-1 和 TLR4 信号通路之间的串扰可能在主动脉瓣的生理胚胎发育以及成年期的主动脉瓣内稳态和功能中发挥关键作用。
