© 1995 American Heart Association, Inc.
Articles |
Sodium Butyrate Inhibits Platelet-Derived Growth Factor–Induced Proliferation of Vascular Smooth Muscle Cells
From the Department of Neurology, University of Texas Health Science Center at Houston (Tex).
Correspondence to Kasturi Ranganna, Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX 77030.
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 ß-PDGF–receptor
(ß-PDGFR). The activated ß-PDGFR physically associated and
phosphorylated signaling molecules such as
ras-GTPase activating protein (GAP) and phospholipase C
(PLC). SB, in the absence of PDGF-BB, caused neither ß-PDGFR
tyrosine phosphorylation nor
phosphorylation and association of GAP and PLC with
ß-PDGFR. PDGF-BB–enhanced activation of receptor intrinsic tyrosine
kinase activity and autophosphorylation of tyrosine
residues of ß-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 PLC with
PDGF-BB–activated ß-PDGFR were unaffected. In addition, SB
did not block PDGF-BB–stimulated, PLC-mediated
production of inositol triphosphate. Similarly,
PDGF-BB–induced ß-PDGFR degradation was unaffected when SMCs were
exposed to PDGF-BB plus SB, and SB by itself had no influence on
ß-PDGFR degradation. Unlike ß-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.
Key Words: sodium butyrate • proliferation • platelet-derived growth factor • smooth muscle cells
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