{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T19:56:13Z","timestamp":1782935773864,"version":"3.54.5"},"reference-count":38,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Allergy"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hereditary angioedema (HAE) is a rare genetic disorder characterized by local, self\u2010limiting edema due to temporary increase in vascular permeability. HAE with normal C1 esterase inhibitor (C1INH) activity includes the form with mutations in the <jats:italic>F12<\/jats:italic> gene encoding for coagulation factor XII (FXII\u2010HAE) 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\u2010arachidonoylglycerol (2\u2010AG) and anandamide (AEA), and eCB\u2010related <jats:italic>N<\/jats:italic>\u2010acylethanolamines [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)]. To date, there are no data on the role of these lipid mediators in FXII\u2010HAE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we analyzed plasma levels of PLC, DAGs, and eCBs in 40 patients with FXII\u2010HAE and 40 sex\u2010 and age\u2010matched healthy individuals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Plasma PLC activity was increased in FXII\u2010HAE patients compared to controls. Concentrations of DAG 18:1\u201320:4, a lipid second messenger produced by PLC, were higher in FXII\u2010HAE compared to controls, and positively correlated with PLC activity and cleaved high molecular kininogen (cHK). Also the concentrations of the DAG metabolite, 2\u2010AG were altered in FXII\u2010HAE. AEA and OEA were decreased in FXII\u2010HAE 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\u2010HAE patients had elevated plasma levels of PLC, which correlated with cHK, but the levels of DAGs and eCBs were the same as controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>BK overproduction and BKR2 activation are linked to alteration of PLCs and their metabolites in patients with FXII\u2010HAE. Our results may pave way to investigations on the functions of these mediators in the pathophysiology of FXII\u2010HAE, and provide new potential biomarkers and therapeutic targets.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.16197","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T14:19:13Z","timestamp":1719497953000},"page":"287-296","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Altered levels of phospholipases C, diacylglycerols, endocannabinoids, and <i>N<\/i>\u2010acylethanolamines in patients with hereditary angioedema due to <scp>FXII<\/scp> mutation"],"prefix":"10.1111","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1839-8873","authenticated-orcid":false,"given":"Anne Lise","family":"Ferrara","sequence":"first","affiliation":[{"name":"Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research University of Naples Federico II, WAO Center of Excellence  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6145-7475","authenticated-orcid":false,"given":"Francesco","family":"Palestra","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research University of Naples Federico II, WAO Center of Excellence  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9343-4622","authenticated-orcid":false,"given":"Fabiana","family":"Piscitelli","sequence":"additional","affiliation":[{"name":"Endocannabinoid Research Group Istituto di Chimica Biomolecolare\u2010Consiglio Nazionale delle Ricerche  Pozzuoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5700-7164","authenticated-orcid":false,"given":"Angelica","family":"Petraroli","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research University of Naples Federico II, WAO Center of Excellence  Naples Italy"},{"name":"Italian Network for Hereditary and Acquired Angioedema  Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8872-8842","authenticated-orcid":false,"given":"Chiara","family":"Suffritti","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Angelo Bianchi Bonomi Hemophilia and Thrombosis Center  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5768-391X","authenticated-orcid":false,"given":"Davide","family":"Firinu","sequence":"additional","affiliation":[{"name":"Italian Network for Hereditary and Acquired Angioedema  Napoli Italy"},{"name":"Internal Medicine, Allergy and Clinical Immunology, Department of Medical Sciences and Public Health University of Cagliari  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9596-6910","authenticated-orcid":false,"given":"Alberto","family":"L\u00f3pez\u2010Lera","sequence":"additional","affiliation":[{"name":"Hospital La Paz Institute for Health Research (IdiPAZ), CIBERER (U754)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3005-9858","authenticated-orcid":false,"given":"Teresa","family":"Caballero","sequence":"additional","affiliation":[{"name":"Allergy Department Hospital Universitario La Paz, Hospital La Paz Institute for Health Research (IdiPAZ), CIBERER (U754)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6084-4577","authenticated-orcid":false,"given":"Konrad","family":"Bork","sequence":"additional","affiliation":[{"name":"Department of Dermatology University Medical Center, Johannes Gutenberg University  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7889-425X","authenticated-orcid":false,"given":"Giuseppe","family":"Spadaro","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research University of Naples Federico II, WAO Center of Excellence  Naples Italy"},{"name":"Italian Network for Hereditary and Acquired Angioedema  Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9849-4701","authenticated-orcid":false,"given":"Gianni","family":"Marone","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research University of Naples Federico II, WAO Center of Excellence  Naples Italy"},{"name":"Institute of Experimental Endocrinology and Oncology \u201cG. 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