In the current study the effect of Silibinin-C-2 , 3-bis (hydrogensuccinate), Disodium salt on cardiovascular differentiation and leukopoiesis of mouse ES cells was investigated. Silibinin is a bioactive substance from milk thistle (Silybum marianum (L.) Gaertn.), and owns cell and organ regeneration-promoting properties.It was demonstrated that Silibinin-stimulated vasculogenesis, the expression of vasculogenic proteins (VEGFR2, HIF-1alpha, VE-Cadherin) and leukopoiesis (CD45+-, CD18+-, and CD68+ -cells) of ES cells, whereas an inhibition of cardiomyogenesis was observed.Silibinin inhibited the Ang II-mediated stimulation of cardiomyogenesis of ES cells as well as the Ang II-mediated increase in contraction frequency and frequency of Ca2+ spikes. However, not by blockage of the AT1 receptor itself, but by inhibition of ERK1/2, p38 and JNK signaling pathways downstream of the AT1 receptor. In adult rat cardiomyocytes Silibinin reversed the inhibition of cell contractility following Ang II treatment. Treatment of differentiating ES cells with Silibinin resulted in NO generation and activation of eNOS within few minutes. Furthermore, activation of the PI3K/AKT and STAT3 signaling pathway was observed. Inhibition of NO generation by L-NAME, STAT3 activation by Stattic, AKT activation by AKT inhibitor VIII and PI3K activation by LY294002 abolished the stimulation of vasculogenesis and leukopoiesis by Silibinin. Stattic inhibited the Silibinin-induced eNOS and AKT activation as well as NO generation. AKT inhibitor VIII inhibited the Silibinin-mediated NO generation and eNOS as well as STAT3 phosphorylation. The PI3K inhibitor LY294002 blunted Silibinin-mediated NO generation, eNOS activation as well as AKT and STAT3 phosphorylation.In conclusion the data of the present study show that Silibinin stimulates vasculogenesis and leukopoiesis of ES cells through a NO-mediated and PI3K/AKT- as well as STAT3-regulated signaling pathway. On the other hand Silibinin prevents cardiomyogenesis through inhibition of the Ang II signaling pathway on the level of the ERK1/2, p38 and JNK signaling cascade.
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