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Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells.

ABSTRACT: Infantile hemangiomas can cause significant morbidity during proliferation, yet there is no U.S. Food and Drug Administration-approved treatment. They are believed to form from hemangioma stem cells, which differentiate toward a hemangioma endothelial cell phenotype. Recently, propranolol has demonstrated effectiveness in treating complicated infantile hemangiomas. The authors hypothesize that propranolol facilitates their involution by altering cellular behavior in both hemangioma endothelial and stem cells.Hemangioma endothelial and stem cells were isolated from resected infantile hemangioma specimens. Cells were treated with 100 ?M propranolol for 48 hours, and apoptosis was determined by the presence of annexin V antibody. Proliferation of stem and endothelial cells was assessed after treatment with 50 or 100 ?M propranolol or vehicle, for 72 and 96 hours, respectively. Adipogenesis was induced in stem cells with and without propranolol. Pro-adipogenic genes PPAR?, PPAR?, C/EBP?, C/EBP?, C/EBP?, RXR?, and RXR? were analyzed by quantitative polymerase chain reaction.Annexin V levels were increased in propranolol-treated endothelial cells but not in stem cells. Proliferation of stem and endothelial cells was inhibited by propranolol in a dose-dependent manner. Propranolol-treated stem cells demonstrated accelerated adipogenesis when compared with untreated controls. Transcript levels of C/EBP? (p < 0.05), RXR? (p < 0.05), and PPAR? (p < 0.02) were significantly increased when treated with 50 or 100 ?M propranolol; and C/EBP? (p < 0.05), RXR? (p < 0.05), and PPAR? (p < 0.01) transcripts were increased when treated with 100 ?M propranolol. C/EBP? transcript levels remained unchanged at either dose.Propranolol increased apoptosis of hemangioma endothelial cells, but not stem cells, and accelerated adipogenesis of hemangioma stem cells. Thus, propranolol likely accelerates involution to fibrofatty residuum.

SUBMITTER: Wong A

PROVIDER: S-EPMC3668332 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells.

Wong Alvin A Hardy Krista L KL Kitajewski Alex M AM Shawber Carrie J CJ Kitajewski Jan K JK Wu June K JK

Plastic and reconstructive surgery 20121101 5

<h4>Background</h4>Infantile hemangiomas can cause significant morbidity during proliferation, yet there is no U.S. Food and Drug Administration-approved treatment. They are believed to form from hemangioma stem cells, which differentiate toward a hemangioma endothelial cell phenotype. Recently, propranolol has demonstrated effectiveness in treating complicated infantile hemangiomas. The authors hypothesize that propranolol facilitates their involution by altering cellular behavior in both heman ...[more]

PMID: 23096601

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Project description:Background Propranolol is a first-line clinical drug for infantile haemangiomas (IH) therapy. Nevertheless, resistance to propranolol is observed in some patients with IH. Circular RNAs (circRNAs) has been increasingly reported to act as a pivotal regulator in tumor progression. However, the underlying mechanism of circRNAs in IH remains unclear. Methods Quantitative real-time polymerase chain reaction was performed to detect Circ_0000915, miR-890 and RNF187 expression. Protein levels were determined using western blot. CCK-8 assay was used to measure cell proliferation. Caspase-3 activity assay and flow cytometry were conducted to determine cell apoptosis. Luciferase reporter assay was carried out to assess the interaction between miR-890 and Circ_0000915 or RNF187. Chromatin immunoprecipitation assay was performed to detect the interaction between STAT3 and Circ_0000915 promoter. Biotin pull-down assay was used to detect the direct interaction between miR-890 and Circ_0000915. In vivo experiments were performed to measure tumor formation. Results Here, we discovered depletion of Circ_0000915 increased propranolol sensitivity of haemangioma derived stem cells (HemSCs) both in vitro and in vivo, whereas forced expression of Circ_0000915 exhibited opposite effects. Mechanistically, Circ_0000915, transcriptionally induced by IL-6/STAT3 pathway, competed with RNF187 for the biding site in miR-890, led to upregulation of RNF187 by acting as a miR-890 “sponge”. Furthermore, silence of miR-890 reversed increased propranolol sensitivity of HemSCs due to Circ_0000915 ablation. Moreover, increased Circ_0000915 and RNF187 levels were observed in IH tissues and positively associated with propranolol resistance, miR-890 exhibited an inverse expression pattern. Conclusion We thereby uncover the activation of IL-6/STAT3/Circ_0000915/miR-890/RNF187 axis in propranolol resistance of IH, and provide therapeutic implications for patients of IH with propranolol resistance. Supplementary Information The online version contains supplementary material available at 10.1186/s40246-022-00416-w.

Project description:Infantile hemangiomas (IHs) are the most common vascular tumor and arise from a hemangioma stem cell (HemSC). Propranolol has proved efficacious for problematic IHs. Propranolol is a nonselective ?-adrenergic receptor (?AR) antagonist that can lower cAMP levels and activate the mitogen-activated protein kinase (MAPK) pathway downstream of ?ARs. We found that HemSCs express ?1AR and ?2AR in proliferating IHs and determined the role of these ?ARs and the downstream pathways in mediating propranolol's effects. In isolated HemSCs, propranolol suppressed cAMP levels and activated extracellular signal-regulated kinase (ERK)1/2 in a dose-dependent fashion. Propranolol, used at doses of <10(-4) M, reduced cAMP levels and decreased HemSC proliferation and viability. Propranolol at ?10(-5) M reduced cAMP levels and activated ERK1/2, and this correlated with HemSC apoptosis and cytotoxicity at ?10(-4) M. Stimulation with a ?AR agonist, isoprenaline, promoted HemSC proliferation and rescued the antiproliferative effects of propranolol, suggesting that propranolol inhibits ?AR signaling in HemSCs. Treatment with a cAMP analog or a MAPK inhibitor partially rescued the HemSC cell viability suppressed by propranolol. A selective ?2AR antagonist mirrored propranolol's effects on HemSCs in a dose-dependent fashion, and a selective ?1AR antagonist had no effect, supporting a role for ?2AR signaling in IH pathobiology. In a mouse model of IH, propranolol reduced the vessel caliber and blood flow assessed by ultrasound Doppler and increased activation of ERK1/2 in IH cells. We have thus demonstrated that propranolol acts on HemSCs in IH to suppress proliferation and promote apoptosis in a dose-dependent fashion via ?2AR perturbation, resulting in reduced cAMP and MAPK activation.The present study investigated the action of propranolol in infantile hemangiomas (IHs). IHs are the most common vascular tumor in children and have been proposed to arise from a hemangioma stem cell (HemSC). Propranolol, a nonselective ?-adrenergic receptor (?AR) antagonist, has proven efficacy; however, understanding of its mechanism of action on HemSCs is limited. The presented data demonstrate that propranolol, via ?AR perturbation, dose dependently suppresses cAMP levels and activated extracellular signal-regulated kinase 1/2. Furthermore, propranolol acts via perturbation of ?2AR, and not ?1AR, although both receptors are expressed in HemSCs. These results provide important insight into propranolol's action in IHs and can be used to guide the development of more targeted therapy.

Project description:BackgroundInfantile hemangioma (IHA) is the most common tumor in infancy. We aimed to explore the effect of propranolol on the expression of microRNA (miR)-424 in IHA tissues and XPTS-1 cells, as well as its molecular mechanism of inhibiting XPTS-1 cell activity.MethodsTumor tissues and peritumoral tissue were collected from 13 IHA patients in Lishui Municipal Central Hospital. The level of miR-424 were detected using real-time quantitative reverse transcription polymerase chain reaction (RT-PCR). Cell counting kit-8 (CCK-8) was used to measure XPTS-1 cell viability. Flow cytometry and transwell were used to detect the apoptosis level and invasion ability of XPTS-1 cells. Western blot was used to measure the protein level of vascular endothelial growth factor-A (VEGFA). The luciferase reporter gene assay detected the targeting relationship between miR-424 and VEGFA.ResultsCompared with normal tissues and human umbilical vein endothelial cells, the expression level of miR-424 in IHA tissues and XPTS-1 cells was significantly reduced (P<0.05). As the concentration of propranolol increased, XPTS-1 cell viability gradually decreased (P<0.05), and the expression level of VEGFA decreased (P<0.05). The expression of miR-424 increased with the time of propranolol treatment (P<0.05). Compared with the control group, treatment with an miR-424 inhibitor resulted in a significant increase in XPTS-1 cell viability and invasion ability (P<0.05), and a decrease in apoptosis (P<0.05). However, both propranolol and miR-424 inhibitor treatment resulted in a partial decrease in XPTS-1 cell viability (P<0.05), and a partial increase in the level of apoptosis (P<0.05). MiR-424 directly targeted VEGFA; the overexpression of miR-424 resulted in a decrease in the VEGFA protein level (P<0.05), while inhibition of miR-424 resulted in an increase in the VEGFA protein level (P<0.05). Compared with the propranolol group, the XPTS-1 cell viability and invasion ability in the propranolol + VEGFA-si group were significantly decreased (P<0.05), while the level of apoptosis increased (P<0.05). Meanwhile, simultaneous miR-424 inhibitor treatment resulted in no difference in cell viability and apoptosis levels compared with the propranolol group, and the invasion ability was partially restored (P<0.05).ConclusionsPropranolol affects the malignant biological behavior of IHA cells by regulating the miR-424/VEGFA axis.

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Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells.

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Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells.

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