Department of Medicine, UCSD, San Diego, California, USA.
Department of Neurological Surgery, University of Chicago, Chicago, Illinois, USA.
J Clin Invest. 2021 Feb 1;131(3). doi: 10.1172/JCI144893.
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.
普萘洛尔是一种具有多种作用的β肾上腺素能阻滞剂，据报道可减少人类脑海绵状血管畸形（CCM）。然而，普萘洛尔尚未在动物模型中进行严格评估，其在 CCM 中的作用机制也尚未确定。我们报告称，普萘洛尔或其 S（-）对映体可显著减少 ccm2 嵌合体斑马鱼的胚胎静脉海绵状瘤，而缺乏β拮抗作用的 R-（+）-普萘洛尔则没有效果。β1肾上腺素能受体的沉默模拟了普萘洛尔在斑马鱼 CCM 模型中的有益作用，而β1选择性拮抗剂美托洛尔也是如此。因此，普萘洛尔通过β1肾上腺素能拮抗作用改善了斑马鱼的海绵状血管畸形。口服普萘洛尔可显著降低两种慢性鼠模型中异常侵袭性 Pdcd10/Ccm3 型 CCM 的病变负担。普萘洛尔或其他β1选择性拮抗剂可能对 CCM 疾病有益。
