To further explore the mechanism underlying valproate induced cardiac malformation, we performed experiments to determine selleck kinase inhibitor the effect of valproate on histone deacetylase activity. Our data indicate that valproate can significantly protein inhibitors inhibit HDAC activity in mouse cardiac myocytes exposed to NaVP. This result is consistent with a recent report that valprotic acid is defined as a novel class of HDAC inhibi tors inducing differentiation of transformed cells. The mechanism underlying the inhibitory action of valproate on HDAC is still unknown. According to our experimental data, we believe that valproate does not inhibit HDAC activities through the intervention of the transcription of HDAC genes.
More likely, valproate inhibits HDAC activi ties directly by binding with the active site of the enzyme as other HDAC inhibitors do.
Although no significant changes were observed in the expression levels of HDACs, GATA4 and Nkx2. 5 in fetal hearts exposed to NaVP, some significant changes were observed in the expression levels of several heart develop ment related transcription factors such as CHF1, MEF2C and Tbx5 in fetal hearts exposed to NaVP. CHF1 is a mem ber of the cardiovascular basic helix loop helix factor fam ily and plays an important role in regulation of ventricular septation in mammalian heart development. MEF2C is a member of the MEF2 family of transcription factors that bind a conserved A T rich DNA sequence asso ciated with most cardiac muscle structural genes and are expressed in cardiogenic precursor cells and differentiated cardiac myocytes during embryogenesis.
Tbx5 is a T box transcription factor that plays a critical role in cardiac development. Tbx5 is expressed in the developing heart in vertebrate embryos during critical stages of morphogenesis and patterning. In human, mutations in the Tbx5 gene have been associated with Holt Oram syndrome, which is char acterized Dacomitinib by developmental anomalies in the heart and fore limbs. The expression pattern of Tbx5 in the heart is very interesting. It is uniformly expressed throughout the entire cardiac crescent early in the developing heart. With the development of the heart, Tbx5 is asymmetrically expressed in the heart.
Expression of Tbx5 in the ventricu lar septum is restricted to the left side and fairly is contiguous with left ventricular free wall expression.
Some studies GSK-3 indicate that these patterns of Tbx5 expression provide an embryologic basis for the prevalence of atrial and ventricu lar septal defects observed in patients with Holt Oram syn drome. Liberatore et al generated transgenic mouse embryos that over express Tbx5 throughout the primitive heart tube and found Sorafenib VEGFR-2 a significant loss of ventricular spe cific gene expression and retardation of ventricular cham ber morphogenesis in these embryos, indicating that Tbx5 plays an essential role in early heart morphogenesis and chamber specific gene expression.