Induction of apoptosis in infantile hemangioma endothelial cells by propranolol

Abstract

Propranolol, a non-selective β-blocker, is emerging as an effective treatment for complicated hemangiomas. The aim of this study was to investigate the molecular mechanism(s) underlying the therapeutic effects of propranolol against hemangiomas, using primary infantile hemangioma endothelial cells (IHECs). IHECs were treated with various concentrations of propranolol and morphological changes and apoptosis were assessed. Changes in the expression levels of apoptosis-related genes were examined. Annexin-V staining revealed that propranolol at 40, 50 and 60 μg/ml caused a concentration-dependent increase in the apoptosis of IHECs. Morphological analyses revealed that exposure to 50 μg/ml propranolol resulted in typical apoptotic changes, including shrinkage, the formation of apoptotic bodies and retention of plasma membrane integrity. Gene expression analyses revealed that propranolol treatment led to a marked increase in the expression of caspase-8, cytochrome c, apoptosis-inducing factor, caspase-3 and poly (ADP-ribose) polymerase 1, as well as a concomitant reduction in lamin B1 expression. Our data collectively demonstrate that propranolol induces apoptosis of IHECs through activation of the intrinsic and extrinsic apoptotic pathways, which represents an important mechanism for its therapeutic effects against infantile hemangiomas.

Adhesion Molecule-Mediated Hippo Pathway Modulates Hemangioendothelioma Cell Behavior

“…Additionally, a specific inhibitor of ␤-adrenergic receptor activation, propranolol, has been found to affect infantile hemangioma growth and apoptosis via activation of caspases 3, 8, and 9 and cytochrome c; upregulation of p53; and increasing the Bax/ BCL-xL ratio (37)(38)(39).…”

Mechanisms of propranolol action in infantile hemangioma

“…49 These results are suggestive of an intrinsic apoptotic pathway mediated by propranolol. However, other studies have found an increase in protein and mRNA levels of caspase-8 32 , indicative of both intrinsic and extrinsic involvement of the apoptotic pathway. At the mRNA level, it was reported that propranolol induces expression of apoptotic genes, such as Bax, p53, caspase-8, and cytochrome c in hemECs that may be responsible for its apoptotic effect.…”

“…49 This is evident upon exposure to 100 mmol/L propranolol in the culture media. 32,49,50 Ji et al also found significant increases in caspase-3 and -9 cleavage products, but not caspase-8 cleavage following propranolol exposure. 49 These results are suggestive of an intrinsic apoptotic pathway mediated by propranolol.…”

“…Many mechanisms have been proposed, though only tested in culture studies, to explain the therapeutic mechanism of propranolol in treating IH. Theories involving vasoconstriction, 28 EC apoptosis via b-ADR signaling 29,30 and the caspase pathway, 31,32 and inhibition of angiogenesis via the modulation of vascular growth factors 30,33,34 have been suggested. This review will emphasize the diverse mechanisms implicated with the therapeutic action of propranolol in the various cell types found in IH.…”

Vaskuläre Malformationen – Diagnostik und Behandlung

“…Daher sprechen vaskuläre Malformationen nicht auf zytostatische Therapien an, wie es z.B. bei infantilen Hämangiomen, den häufigsten vaskulären Tumoren, der Fall ist [4]. Da vaskuläre Malformationen häufig mit vaskulären Tumoren verwechselt werden, kommt es in ca.…”