Role of Endothelial G Protein-Coupled Receptor Kinase 2 in Angioedema

被引：24

作者：

Gambardella, Jessica ^{[1
,4
,5
,6
]}

Sorriento, Daniela ^{[1
]}

Bova, Maria ^{[2
,3
]}

Rusciano, Mariarosaria ^{[7
,8
]}

Loffredo, Stefania ^{[2
,3
]}

Wang, Xujun ^{[4
,5
]}

Petraroli, Angelica ^{[2
,3
]}

Carucci, Laura ^{[2
,3
]}

Mormile, Ilaria ^{[2
,3
]}

Oliveti, Marco ^{[8
]}

Morelli, Marco Bruno ^{[4
,5
]}

Fiordelisi, Antonella ^{[1
]}

Spadaro, Giuseppe ^{[2
,3
]}

Campiglia, Pietro ^{[9
]}

Sala, Marina ^{[9
]}

Trimarco, Bruno ^{[1
,6
]}

Iaccarino, Guido ^{[1
]}

Santulli, Gaetano ^{[1
,4
,5
,6
]}

Ciccarelli, Michele ^{[8
]}

机构：

[1] Univ Naples Federico II, Dept Adv Biomed Sci, Naples, NA, Italy

[2] Univ Naples Federico II, Dept Translat Med Sci, Naples, NA, Italy

[3] Univ Naples Federico II, Interdept Ctr Res Basic & Clin Immunol Sci, Naples, NA, Italy

[4] Montefiore Univ Hosp, Albert Einstein Coll Med, Wilf Family Cardiovasc Res Inst, Div Cardiol,Dept Med, Bronx, NY USA

[5] Montefiore Univ Hosp, Albert Einstein Coll Med, Dept Mol Pharmacol, Fleischer Inst Diabet & Metab FIDAM, Bronx, NY USA

[6] Int Translat Res & Med Educ Consortium ITME, Naples, NA, Italy

[7] Montevergine Hosp, Mercogliano, Italy

[8] Univ Salerno, Dept Med & Surg, Salerno, Italy

[9] Univ Salerno, Dept Pharmaceut Sci, Div Biomed, Salerno, Italy

来源：

HYPERTENSION | 2020年 / 76卷 / 05期

基金：

美国国家卫生研究院;

关键词：

angioedema; atherosclerosis; bradykinin; endothelium; phenotype; HEREDITARY ANGIOEDEMA; NITRIC-OXIDE; BRADYKININ RECEPTORS; MUTATIONAL SPECTRUM; GRK2; EXPRESSION; PATHOPHYSIOLOGY; PERMEABILITY; DEGRADATION; TRAFFICKING;

D O I：

10.1161/HYPERTENSIONAHA.120.15130

中图分类号：

R6 [外科学];

学科分类号：

1002 ; 100210 ;

摘要：

Excessive BK (bradykinin) stimulation is responsible for the exaggerated permeabilization of the endothelium in angioedema. However, the molecular mechanisms underlying these responses have not been investigated. BK receptors are Gq-protein-coupled receptors phosphorylated by GRK2 (G protein-coupled receptor kinase 2) with a hitherto unknown biological and pathophysiological significance. In the present study, we sought to identify the functional role of GRK2 in angioedema through the regulation of BK signaling. We found that the accumulation of cytosolic Ca(2+)in endothelial cells induced by BK was sensitive to GRK2 activity, as it was significantly augmented by inhibiting the kinase. Accordingly, permeabilization and NO production induced by BK were enhanced, as well. In vivo, mice with reduced GRK2 levels in the endothelium (Tie2-CRE/GRK2(fl+/fl-)) exhibited an increased response to BK in terms of vascular permeability and extravasation. Finally, patients with reduced GRK2 levels displayed a severe phenotype of angioedema. Taken together, these findings establish GRK2 as a novel pivotal regulator of BK signaling with an essential role in the pathophysiology of vascular permeability and angioedema.

引用

页码：1625 / 1636

页数：12

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