Sodium Butyrate Inhibits Platelet-Derived Growth Factor–Induced Proliferation of Vascular Smooth Muscle Cells

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Abstract
Sodium butyrate (SB), a naturally occurring short-chain fatty acid, was investigated for its therapeutic value as an antiproliferative agent for vascular smooth muscle cells (SMCs). At 5-mmol/L concentration, SB had no significant effect on rat SMC proliferation. However, at the same concentration, SB inhibited platelet-derived growth factor (PDGF)-AA–, -AB–, and -BB–induced proliferation of SMCs. Exposure of SMCs to PDGF-BB resulted in activation of receptor intrinsic tyrosine kinase activity and autophosphorylation of β-PDGF–receptor (β-PDGFR). The activated β-PDGFR physically associated and phosphorylated signaling molecules such as ras -GTPase activating protein (GAP) and phospholipase Cγ (PLCγ). SB, in the absence of PDGF-BB, caused neither β-PDGFR tyrosine phosphorylation nor phosphorylation and association of GAP and PLCγ with β-PDGFR. PDGF-BB–enhanced activation of receptor intrinsic tyrosine kinase activity and autophosphorylation of tyrosine residues of β-PDGFR were unaffected by SB irrespective of whether SMCs were preincubated with SB before exposure to PDGF-BB plus SB or incubated concomitantly with PDGF-BB plus SB. Likewise, phosphorylation and association of GAP and PLCγ with PDGF-BB–activated β-PDGFR were unaffected. In addition, SB did not block PDGF-BB–stimulated, PLCγ-mediated production of inositol triphosphate. Similarly, PDGF-BB–induced β-PDGFR degradation was unaffected when SMCs were exposed to PDGF-BB plus SB, and SB by itself had no influence on β-PDGFR degradation. Unlike β-PDGFR kinase activity, mitogen-activated protein kinase (MAP-kinase) activity was stimulated by SB by about 2.7-fold. Exposure of SMCs to PDGF-BB caused an ≈11.4-fold increase in MAP-kinase activity and this increase in activity was not significantly affected when cells were coincubated with PDGF-BB and SB (10.3-fold). However, pretreatment of SMCs with SB for 30 minutes and subsequent incubation in PDGF-BB plus SB abolished most of the PDGF-BB–induced MAP-kinase activity (4.6-fold). Transcription of growth response genes such as c- fos , c- jun , and c- myc were induced by PDGF-BB, and their induction was suppressed, particularly c- myc , by incubating SMCs with PDGF-BB plus SB. Similarly, preincubation of cells with SB for 30 minutes and subsequent incubation in PDGF-BB plus SB diminished PDGF-BB–induced transcription of c- fos , c- jun , and c- myc . However, SB by itself had no significant effect on c- fos , c- jun , and c- myc transcription. Our data suggest that the inhibition of PDGF-BB–induced proliferation of SMCs by SB involves MAP-kinase–regulated events as well as transcription of growth-response genes.