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首页> 外文期刊>Journal of Cardiovascular Development and Disease >Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis
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Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis

机译：NOTCH信号与人类主动脉瓣疾病发病机制中生物力学之间的串扰

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Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV) and calcific aortic valve disease. Because calcific nodules manifest on the fibrosa side of the cusp in low fluidic oscillatory shear stress (OSS), elucidating pathogenesis requires approaches that consider both molecular and mechanical factors. Therefore, we examined the relationship between NOTCH loss of function (LOF) and biomechanical indices in healthy and diseased human aortic valve interstitial cells (AVICs). An orbital shaker system was used to apply cyclic OSS, which mimics the cardiac cycle and hemodynamics experienced by AVICs in vivo. NOTCH LOF blocked OSS-induced cell alignment in human umbilical vein endothelial cells (HUVECs), whereas AVICs did not align when subjected to OSS under any conditions. In healthy AVICs, OSS resulted in decreased elastin (ELN) and α-SMA (ACTA2). NOTCH LOF was associated with similar changes, but in diseased AVICs, NOTCH LOF combined with OSS was associated with increased α-SMA expression. Interestingly, AVICs showed relatively higher expression of NOTCH2 compared to NOTCH1. Biomechanical interactions between endothelial and interstitial cells involve complex NOTCH signaling that contributes to matrix homeostasis in health and disorganization in disease.
机译：主动脉瓣疾病是与重大死亡率相关的新兴公共卫生问题。 NOTCH1中功能突变的丧失会导致双尖瓣主动脉瓣（BAV）和钙化主动脉瓣疾病。由于钙化结节在低流体振荡剪切应力（OSS）中出现在尖瓣的纤维侧，因此阐明发病机理需要同时考虑分子和机械因素的方法。因此，我们检查了健康和患病的人主动脉瓣间质细胞（AVIC）中的NOTCH功能丧失（LOF）和生物力学指标之间的关系。轨道振动器系统用于应用循环OSS，该OSS模仿了AVIC在体内所经历的心动周期和血液动力学。 NOTCH LOF阻断了人脐静脉内皮细胞（HUVEC）中OSS诱导的细胞排列，而在任何条件下接受OSS时，AVIC都不排列。在健康的中航工业公司中，OSS导致弹性蛋白（ELN）和α-SMA（ACTA2）下降。 NOTCH LOF与相似的变化有关，但是在患病的中风患者中，NOTCH LOF与OSS联合使用与α-SMA表达增加有关。有趣的是，与NOTCH1相比，中航工业公司的NOTCH2表达相对较高。内皮细胞和间质细胞之间的生物力学相互作用涉及复杂的NOTCH信号传导，有助于健康中的基质稳态和疾病的紊乱。

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