SODIUM-BUTYRATE IS A POTENT MODULATOR OF SMOOTH-MUSCLE CELL-PROLIFERATION AND GENE-EXPRESSION

Sodium butyrate is a small, naturally occurring molecule with demonstr ated activity on cell growth and differentiation. However, its effect on smooth muscle cells had not been examined, We have found that sodiu m butyrate and its more stable in vivo analogue tributyrin are potent DNA synthesis and cell proliferation inhibitors, The inhibitory activi ty of sodium butyrate was not mediated by an elevation of endogenous c AMP levels, a known pathway involved in SMC growth-arrest and maintena nce of the contractile phenotype, Consistent with the concept that its activity is mediated by a cAMP-independent pathway, butyrate was able to augment the maximum DNA synthesis inhibitory effect of various age nts that elevated intracellular cAMP levels, Additionally, butyrate pr esent for just the initial 8 h or present as late as 16 h after serum addition was able to inhibit DNA synthesis, By contrast, the cAMP anal ogue, 8Br-cAMP had to be present throughout the entire G(0), to S phas e of the cell cycle to effectively inhibit DNA synthesis, These result s indicated that sodium butyrate inhibited SMC growth through a cAMP-i ndependent mechanism. We also found that sodium butyrate was unable to abrogate the expression of the serum-inducible genes c-fos, c-myc, Ki -Ras and PS4, but was able to directly stimulate the expression of PS4 and thrombospondin, These results indicate that a number of important early G(1) events initiated by serum growth factors are unaltered by sodium butyrate and that this compound is able to directly stimulate t he expression of certain genes normally associated with SMC proliferat ion.