curcumin and Heart-Defects--Congenital

The osteogenic differentiation of human aortic valve interstitial cells (hVICs) is the key cellular mechanism of calcified aortic valve disease (CAVD). This study aimed to explore how curcumin (CCM) inhibits the osteogenic differentiation of hVICs and elucidate the molecular mechanisms involved. In this study, CCM inhibited the osteogenic differentiation of hVICs under osteogenic medium (OM) conditions by reversing the OM-induced increase in calcified nodule formation and osteogenesis-specific markers (ALP and Runx2). RNA sequencing identified 475 common differentially expressed genes with Venn diagrams of the different groups. Kyoto Encyclopedia of Genes and Genomes enrichment revealed that the CCM inhibition of hVIC osteogenic differentiation was enriched in the NF-κB, PI3K-AKT, TNF, Jak-STAT, and MAPK signaling pathways. In addition, CCM suppressed the phosphorylation of ERK, IκBα, AKT, and interfered with the translocation of P65 into the cell nucleus in hVICs under OM culture conditions. In conclusion, CCM inhibited the osteogenic differentiation of hVICs via interfering with the activation of NF-κB/AKT/ERK signaling pathways. Our findings provide novel insights into a critical role for CCM in CAVD progression and shed new light on CCM-directed therapeutics for CAVD.

Topics: Aortic Valve; Aortic Valve Stenosis; Bicuspid Aortic Valve Disease; Calcinosis; Curcumin; Heart Defects, Congenital; Heart Valve Diseases; Humans; NF-kappa B; Proto-Oncogene Proteins c-akt

Histone acetylation plays an important role in heart development. However, the mechanism(s) remains unclear. This study was designed to evaluate the effect of curcumin-caused histone hypo-acetylation on the development of mouse embryonic heart and the expression of cardiac transcription factors in vivo. The results showed that curcumin treatment significantly decreased histone acetylase activity and histone acetylation level in mouse embryonic heart. In curcumin-treated mice, the hearts on E11.5 were smaller with thinner ventricular wall and a delayed development of trabeculae and ventricular septum compared with the controls. The ventricular septum was complete on E14.5; however, the ventricular wall and septum were thinner with fewer trabeculae than those in the controls. On E17.5, the cardiac structure appeared normal, but the ventricular wall and septum were thinner. The expression of GATA4, Nkx2.5 and Mef2c in the heart on E11.5 and E14.5 was decreased significantly as compared to the controls. There was no significant difference in Mef2c expression on E17.5 between curcumin-treated group and the controls, while GATA4 and Nkx2.5 expression remained significantly reduced. These results indicate that inhibition of histone acetylation by curcumin can reduce the expression of the cardiac transcription factors resulting in an abnormal heart development in mice.

Topics: Acetylation; Animals; Curcumin; Down-Regulation; GATA4 Transcription Factor; Gene Expression Regulation, Developmental; Gestational Age; Heart; Heart Defects, Congenital; Histones; Homeobox Protein Nkx-2.5; Homeodomain Proteins; Lysine; MEF2 Transcription Factors; Mice, Inbred ICR; Myocardium; p300-CBP Transcription Factors; Time Factors; Transcription Factors

Alcohol exposure during pregnancy may cause congenital heart disease (CHD). In our previous studies, we found that alcohol selectively increased acetylation of histone H3 at lysine 9 (H3K9) and enhanced the expression of heart development-related genes in cardiac progenitor cells. The objective of this study is to investigate the protective effects of histone acetyltransferases (HATs) inhibitor, curcumin, on histone hyperacetylation and the over-expression of heart development genes induced by alcohol. Western blot analysis was employed to detect the acetylation levels of histone H3K9 and real-time PCR was applied to measure the expressions of heart development-related transcription factors, GATA4, Mef2c and Tbx5 (GMT). Our results showed that alcohol increased the acetylation of H3K9 by 2.76-fold (P<0.05) and significantly enhanced the expression of GATA4 and Mef2c (P<0.05). When cells were treated with alcohol plus 25 μM curcumin, the hyperacetylation of H3K9 and over-expression of GATA4 and Mef2c by alcohol was reversed. These data indicate that curcumin can correct the over-expression of cardiac genes by reversing the alcohol induced hyperacetylation of histone H3 at lysine 9 in cardiac progenitor cells, suggesting that curcumin is protective against alcohol-induced cardiac gene over-expression that may result in heart malformations.

Topics: Acetylation; Animals; Cell Line; Curcumin; Ethanol; Heart; Heart Defects, Congenital; Histones; Lysine; Mice; Myoblasts, Cardiac; Transcription Factors