Abstract：
BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder characterized by local, self-limiting edema due to temporary increase in vascular permeability. HAE with normal C1 esterase inhibitor (C1INH) activity includes the form with mutations in the F12 gene encoding for coagulation factor XII (FXII-HAE) causing an overproduction of bradykinin (BK) leading to angioedema attack. BK binding to B2 receptors (BK2R) leads to an activation of phospholipase C (PLC) and subsequent generation of second messengers: diacylglycerols (DAGs) and possibly the endocannabinoids (eCBs), 2-arachidonoylglycerol (2-AG) and anandamide (AEA), and eCB-related N-acylethanolamines [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)]. To date, there are no data on the role of these lipid mediators in FXII-HAE.
METHODS: Here, we analyzed plasma levels of PLC, DAGs, and eCBs in 40 patients with FXII-HAE and 40 sex- and age-matched healthy individuals.
RESULTS: Plasma PLC activity was increased in FXII-HAE patients compared to controls. Concentrations of DAG 18:1-20:4, a lipid second messenger produced by PLC, were higher in FXII-HAE compared to controls, and positively correlated with PLC activity and cleaved high molecular kininogen (cHK). Also the concentrations of the DAG metabolite, 2-AG were altered in FXII-HAE. AEA and OEA were decreased in FXII-HAE patients compared to controls; by contrast, PEA, was increased. The levels of all tested mediators did not differ between symptomatic and asymptomatic patients. Moreover, C1INH-HAE patients had elevated plasma levels of PLC, which correlated with cHK, but the levels of DAGs and eCBs were the same as controls.
CONCLUSIONS: BK overproduction and BKR2 activation are linked to alteration of PLCs and their metabolites in patients with FXII-HAE. Our results may pave way to investigations on the functions of these mediators in the pathophysiology of FXII-HAE, and provide new potential biomarkers and therapeutic targets.
METHODS: Here, we analyzed plasma levels of PLC, DAGs, and eCBs in 40 patients with FXII-HAE and 40 sex- and age-matched healthy individuals.
RESULTS: Plasma PLC activity was increased in FXII-HAE patients compared to controls. Concentrations of DAG 18:1-20:4, a lipid second messenger produced by PLC, were higher in FXII-HAE compared to controls, and positively correlated with PLC activity and cleaved high molecular kininogen (cHK). Also the concentrations of the DAG metabolite, 2-AG were altered in FXII-HAE. AEA and OEA were decreased in FXII-HAE patients compared to controls; by contrast, PEA, was increased. The levels of all tested mediators did not differ between symptomatic and asymptomatic patients. Moreover, C1INH-HAE patients had elevated plasma levels of PLC, which correlated with cHK, but the levels of DAGs and eCBs were the same as controls.
CONCLUSIONS: BK overproduction and BKR2 activation are linked to alteration of PLCs and their metabolites in patients with FXII-HAE. Our results may pave way to investigations on the functions of these mediators in the pathophysiology of FXII-HAE, and provide new potential biomarkers and therapeutic targets.
摘要：
背景：遗传性血管性水肿（HAE）是一种罕见的遗传性疾病，由于血管通透性暂时增加引起的自限性水肿。具有正常C1酯酶抑制剂（C1INH）活性的HAE包括在编码凝血因子XII（FXII-HAE）的F12基因中具有突变的形式，导致缓激肽（BK）的过度产生，从而导致血管性水肿发作。BK与B2受体（BK2R）的结合导致磷脂酶C（PLC）的激活，并随后产生第二信使：二酰基甘油（DAG）和可能的内源性大麻素（eCB），2-花生四酰基甘油（2-AG）和anandamide（AEA），和eCB相关的N-酰基乙醇胺[棕榈酰乙醇胺(PEA)和油酰乙醇胺(OEA)]。迄今为止,没有关于这些脂质介质在FXII-HAE中的作用的数据。
方法：这里，我们分析了PLC的血浆水平,DAG,和eCBs在40名FXII-HAE患者和40名性别和年龄匹配的健康个体中。
结果：与对照组相比，FXII-HAE患者的血浆PLC活性增加。由PLC产生的脂质第二信使DAG18：1-20：4的浓度，与对照组相比，FXII-HAE中的含量更高，与PLC活性和裂解的高分子激肽原（cHK）呈正相关。还有DAG代谢物的浓度，2-AG在FXII-HAE中改变。与对照组相比，FXII-HAE患者的AEA和OEA降低；相比之下，PEA,增加了。所有测试介质的水平在有症状和无症状患者之间没有差异。此外，C1INH-HAE患者的血浆PLC水平升高，与cHK相关，但DAG和eCBs的水平与对照组相同。
结论：BK过度产生和BKR2激活与FXII-HAE患者PLC及其代谢产物的改变有关。我们的结果可能为研究这些介质在FXII-HAE病理生理学中的功能铺平道路，并提供新的潜在生物标志物和治疗靶点。
方法：这里，我们分析了PLC的血浆水平,DAG,和eCBs在40名FXII-HAE患者和40名性别和年龄匹配的健康个体中。
结果：与对照组相比，FXII-HAE患者的血浆PLC活性增加。由PLC产生的脂质第二信使DAG18：1-20：4的浓度，与对照组相比，FXII-HAE中的含量更高，与PLC活性和裂解的高分子激肽原（cHK）呈正相关。还有DAG代谢物的浓度，2-AG在FXII-HAE中改变。与对照组相比，FXII-HAE患者的AEA和OEA降低；相比之下，PEA,增加了。所有测试介质的水平在有症状和无症状患者之间没有差异。此外，C1INH-HAE患者的血浆PLC水平升高，与cHK相关，但DAG和eCBs的水平与对照组相同。
结论：BK过度产生和BKR2激活与FXII-HAE患者PLC及其代谢产物的改变有关。我们的结果可能为研究这些介质在FXII-HAE病理生理学中的功能铺平道路，并提供新的潜在生物标志物和治疗靶点。
