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2 results on '"Bruno Morelli, M."'

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

Author

Stefania Loffredo, Maria Bova, Jessica Gambardella, Xujun Wang, Gaetano Santulli, Michele Ciccarelli, Guido Iaccarino, Bruno Trimarco, Mariarosaria Rusciano, Angelica Petraroli, Giuseppe Spadaro, Laura Carucci, Marco Bruno Morelli, Antonella Fiordelisi, Pietro Campiglia, Ilaria Mormile, Marina Sala, Daniela Sorriento, Marco Oliveti, Gambardella, J., Sorriento, D., Bova, M., Rusciano, M., Loffredo, S., Wang, X., Petraroli, A., Carucci, L., Mormile, I., Oliveti, M., Bruno Morelli, M., Fiordelisi, A., Spadaro, G., Campiglia, P., Sala, M., Trimarco, B., Iaccarino, G., Santulli, G., and Ciccarelli, M.

Subjects
0301 basic medicine, Endothelium, G-Protein-Coupled Receptor Kinase 2, Bradykinin, Vascular permeability, 030204 cardiovascular system & hematology, Pharmacology, Nitric Oxide, Article, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Internal Medicine, medicine, Animals, Humans, Angioedema, Phosphorylation, Receptor, Atherosclerosis, Phenotype, G protein-coupled receptor kinase, biology, Kinase, Beta adrenergic receptor kinase, Endothelial Cells, 030104 developmental biology, medicine.anatomical_structure, chemistry, Atherosclerosi, biology.protein, Calcium, Endothelium, Vascular, medicine.symptom, Signal Transduction
Abstract

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.

Published
2020

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

Author

Gambardella J, Sorriento D, Bova M, Rusciano M, Loffredo S, Wang X, Petraroli A, Carucci L, Mormile I, Oliveti M, Bruno Morelli M, Fiordelisi A, Spadaro G, Campiglia P, Sala M, Trimarco B, Iaccarino G, Santulli G, and Ciccarelli M

Subjects
Animals, Calcium metabolism, Endothelial Cells drug effects, Endothelial Cells metabolism, Endothelium, Vascular drug effects, Humans, Mice, Nitric Oxide metabolism, Phosphorylation drug effects, Signal Transduction drug effects, Angioedema metabolism, Bradykinin pharmacology, Endothelium, Vascular metabolism, G-Protein-Coupled Receptor Kinase 2 metabolism
Abstract

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.

Published
2020
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