Untitled

Abstract

Excessive proliferation of vascular smooth muscle cells (VSMCs) is a critical element in the development of several vascular pathologies, particularly in atherosclerosis and in restenosis due to angioplasty. We have shown that butyrate, a powerful antiproliferative agent, a strong promoter of cell differentiation and an inducer of apoptosis inhibits VSMC proliferation at physiological concentrations with no cytotoxicity. In the present study, we have used cDNA array technology to unravel the molecular basis of the antiproliferative effect of butyrate on VSMCs. To assess the involvement of gene expression in butyrate-inhibited VSMC proliferation, proliferating VSMCs were exposed to 5 mmol/l butyrate 1 through 5 days after plating. Expression profiles of 1.176 genes representing different functional classes in untreated control and butyrate treated VSMCs were compared. A total of 111 genes exhibiting moderate (2.0-5.0 fold) to strong (> 5.0 fold) differential expression were identified. Analysis of these genes indicates that butyrate treatment mainly alters the expression of four different functional classes of genes, which include: 43 genes implicated in cell growth and differentiation, 13 genes related to stress response, 11 genes associated with vascular function and 8 genes normally present in neuronal cells. Examination of differentially expressed cell growth and differentiation related genes indicate that butyrate-inhibited VSMC proliferation appears to involve down-regulation of genes that encode several positive regulators of cell growth and up-regulation of some negative regulators of growth or differentiation inducers. Some of the down-regulated genes include proliferating cell nuclear antigen (PCNA), retinoblastoma susceptibility related protein p130 (pRb), cell division control protein 2 homolog (cdc2), cyclin B1, cell division control protein 20 homolog (p55cdc), high mobility group (HMG) 1 and 2 and several others. Whereas the up-regulated genes include cyclin D1, p21WAF1, p141NK4B/p15INK5B, Clusterin, inhibitor of DNA binding 1 (ID1) and others. On the other hand, butyrate-responsive stress-related genes include some of the members of heat shock protein (HSP), glutathione-s-transferase (GST), glutathione peroxidase (GSH-PXs) and cytochrome P450 (CYP) families. Additionally, several genes related to vascular and neuronal function are also responsive to butyrate treatment. Although involvement of genes that encode stress response, vascular and neuronal functional proteins in cell proliferation is not clear, cDNA expression array data appear to suggest that they may play a role in the regulation of cell proliferation. However, cDNA expression profiles indicate that butyrate-inhibited VSMC proliferation involves combined action of a proportionally large number of both positive and negative regulators of growth, which ultimately causes growth arrest of VSMCs. Furthermore, these butyrate-induced differential gene expression changes are not only consistent with the antiproliferative effect of butyrate but a...

Effect of a probiotic beverage consumption (Enterococcus faecium CRL 183 and Bifidobacterium longum ATCC 15707) in rats with chemically induced colitis

“…The amount of SCFA can be essentially influenced by three factors: diet composition, intestinal microbiota and intestinal area [108,109]. SCFA are not only considered an important substrate for the enterocytes, but are also able to modulate the inflammatory response [25,110,111]. Fig 6 shows SCFA concentration in the animals’ colon.…”

Quantification of Transcriptome Responses of the Rumen Epithelium to Butyrate Infusion using RNA-seq Technology

“…The majority of our knowledge on regulatory impact of butyrate on global gene expression is derived from in vitro studies and observations 6,31,32. However, caution in interpretation of in vitro data and application of knowledge gained in vitro to in vivo models is warranted.…”

“…SCFAs, such as butyrate, are known to promote rumen development and stimulate the proliferation of rumen epithelial cells in vivo 33. However, butyrate inhibits the proliferation of epithelial cells of the large intestine, rumen and kidney by down- regulating genes controlling cell proliferation in vitro 2,32. Butyrate also induces apoptosis and differentiation of tumor cells 34,35.…”

Alternative Splicing Regulated by Butyrate in Bovine Epithelial Cells

“…This was supported by our observation that the total number of genes transcribed in butyrate-treated cells (mean ± sd =19,322±155) was significantly higher than in untreated control cells (17,626±125) ( P <0.00001). Transcriptional effects of butyrate have been extensively investigated in various cell types, in both in vitro and in vivo models [19], [23]–[25]. Indeed, previous studies have demonstrated that butyrate down-regulates genes controlling cell proliferation in vitro , resulting in the inhibition of the proliferation of epithelial cells [25], [26].…”