PUBLICATION
Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism
- Authors
- Li, W., Shenkar, R., Detter, M.R., Moore, T., Benavides, C.R., Lightle, R., Girard, R., Hobson, N., Cao, Y., Li, Y., Griffin, E., Gallione, C., Zabramski, J.M., Ginsberg, M.H., Marchuk, D.A., Awad, I.A.
- ID
- ZDB-PUB-201212-22
- Date
- 2020
- Source
- The Journal of Clinical Investigation 131(3): (Journal)
- Registered Authors
- Keywords
- Mouse models, Stroke, Vascular Biology, endothelial cells
- MeSH Terms
-
- Apoptosis Regulatory Proteins/genetics
- Apoptosis Regulatory Proteins/metabolism
- Mice
- Programmed Cell Death 1 Receptor/genetics
- Programmed Cell Death 1 Receptor/metabolism
- Male
- Female
- Zebrafish
- Propranolol/pharmacology*
- Hemangioma, Cavernous, Central Nervous System*/chemically induced
- Hemangioma, Cavernous, Central Nervous System*/drug therapy
- Hemangioma, Cavernous, Central Nervous System*/genetics
- Hemangioma, Cavernous, Central Nervous System*/metabolism
- Proto-Oncogene Proteins/genetics
- Proto-Oncogene Proteins/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Adrenergic beta-1 Receptor Antagonists/adverse effects*
- Adrenergic beta-1 Receptor Antagonists/pharmacology
- G-Protein-Coupled Receptor Kinase 2/genetics
- G-Protein-Coupled Receptor Kinase 2/metabolism
- Receptors, Adrenergic, beta-2/genetics
- Receptors, Adrenergic, beta-2/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice, Knockout
- Animals
- PubMed
- 33301422 Full text @ Journal of Clin. Invest.
Citation
Li, W., Shenkar, R., Detter, M.R., Moore, T., Benavides, C.R., Lightle, R., Girard, R., Hobson, N., Cao, Y., Li, Y., Griffin, E., Gallione, C., Zabramski, J.M., Ginsberg, M.H., Marchuk, D.A., Awad, I.A. (2020) Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism. The Journal of Clinical Investigation. 131(3).
Abstract
Propranolol, a pleiotropic β-adrenergic blocker, was anecdotally reported to reduce cerebral cavernous malformations (CCM) in humans. However, propranolol has neither been rigorously evaluated in animal models nor was its mechanism of action in CCM defined. We report that propranolol or its S(-) enantiomer dramatically reduced embryonic venous cavernomas in ccm2 mosaic zebrafish, whereas R-(+)-propranolol, lacking β-antagonism, had no effect. Silencing of β1, but not β2, adrenergic receptor mimicked the beneficial effects of propranolol in a zebrafish CCM model as did a β1-selective antagonist, metoprolol. Thus, propranolol ameliorates cavernous malformations by β1 adrenergic antagonism in zebrafish. Oral propranolol significantly reduced lesion burden in two chronic murine models of the exceptionally aggressive Pdcd10/Ccm3 form of CCM. Propranolol or other β1-selective antagonists may be beneficial in CCM disease.
Errata / Notes
This article is corrected by ZDB-PUB-220906-267 .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping