Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models.

Abstract

Propranolol, a pleiotropic β-adrenergic blocker, has been anecdotally reported to reduce cerebral cavernous malformations (CCMs) in humans. However, propranolol has not been rigorously evaluated in animal models, nor has its mechanism of action in CCM been 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 the β1, but not β2, adrenergic receptor mimicked the beneficial effects of propranolol in a zebrafish CCM model, as did the β1-selective antagonist metoprolol. Thus, propranolol ameliorated cavernous malformations by β1 adrenergic antagonism in zebrafish. Oral propranolol significantly reduced lesion burden in 2 chronic murine models of the exceptionally aggressive Pdcd10/Ccm3 form of CCM. Propranolol or other β1-selective antagonists may be beneficial in CCM disease.

• Authors: Wenqing Li, Robert Shenkar, Mathew R Detter, Thomas Moore, Christian Benavides, Rhonda Lightle, Romuald Girard, Nicholas Hobson, Ying Cao, Yan Li, Erin Griffin, Carol Gallione, Joseph M Zabramski, Mark H Ginsberg, Douglas A Marchuk, Issam A Awad
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 3 (02 01 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 33301422 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ADRB2 protein, mouse
• Adrenergic beta-1 Receptor Antagonists
• Apoptosis Regulatory Proteins
• Membrane Proteins
• PDCD10 protein, mouse
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Proto-Oncogene Proteins
• Receptors, Adrenergic, beta-2
• Zebrafish Proteins
• pdcd10a protein, zebrafish
• Propranolol
• GRK2 protein, mouse
• G-Protein-Coupled Receptor Kinase 2

Topics

• Adrenergic beta-1 Receptor Antagonists (adverse effects, pharmacology)
• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Female
• G-Protein-Coupled Receptor Kinase 2 (genetics, metabolism)
• Hemangioma, Cavernous, Central Nervous System (chemically induced, drug therapy, genetics, metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Programmed Cell Death 1 Receptor (genetics, metabolism)
• Propranolol (pharmacology)
• Proto-Oncogene Proteins (genetics, metabolism)
• Receptors, Adrenergic, beta-2 (genetics, metabolism)
• Zebrafish
• Zebrafish Proteins (genetics, metabolism)