%0 Journal Article
%T Altered levels of phospholipases C, diacylglycerols, endocannabinoids, and N-acylethanolamines in patients with hereditary angioedema due to FXII mutation.
%A Ferrara AL
%A Palestra F
%A Piscitelli F
%A Petraroli A
%A Suffritti C
%A Firinu D
%A López-Lera A
%A Caballero T
%A Bork K
%A Spadaro G
%A Marone G
%A Di Marzo V
%A Bova M
%A Loffredo S
%J Allergy
%V 0
%N 0
%D 2024 Jun 27
%M 38935036
%F 14.71
%R 10.1111/all.16197
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>Here, we analyzed plasma levels of PLC, DAGs, and eCBs in 40 patients with FXII-HAE and 40 sex- and age-matched healthy individuals.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.