Published online before print June 21, 2001, doi: 10.1161/hh1301.093615
© 2001 American Heart Association, Inc.
Cellular Biology |
Redox Regulation of Vascular Smooth Muscle Cell Differentiation
From the Heart and Lung Institute (B.S., S.M., H.G., S.F., M.A.C., P.J.G.-C., N.A.F.) and the Department of Pediatrics, Ohio State University (K.R.C.), Columbus, Ohio.
Correspondence to N.A. Flavahan, PhD, Heart and Lung Institute, Room 110E, 473 W 12th Ave, Columbus OH 43210. E-mail flavahan-1{at}medctr.osu.edu
Abstract
Abstract—Experiments
were performed to determine the role of reactive oxygen species (ROS)
in regulating vascular smooth muscle cell (VSMC)
phenotype. After quiescence, cultured human VSMCs increased
their expression of differentiation proteins (
-actin, calponin, and
SM1 and SM2 myosin), but not ß-actin. ROS activity, determined using
the H2O2-sensitive probe
dichlorodihydrofluorescein
(DCF), remained high in quiescent cells and was inhibited by catalase
(3000 U/mL) or by N-acetylcysteine (NAC, 2 to 20 mmol/L). A
superoxide dismutase mimic (SOD; MnTMPyP, 25 µmol/L) or SOD plus low
concentrations of NAC (SODNAC2, 2 mmol/L) increased DCF
fluorescence, which was inhibited by catalase or by NAC (10 to
20 mmol/L). Inhibition of ROS activity (by catalase or NAC)
decreased the baseline expression of differentiation proteins, whereas
elevation of ROS (by SOD or SODNAC2) increased expression of the
differentiation markers. The latter effect was blocked by catalase or
by NAC (10 to 20 mmol/L). None of the treatments altered ß-actin
expression. SODNAC2-treated cells demonstrated contractions to
endothelin that were absent in proliferating cells. p38
Mitogen-activated protein kinase (MAPK) activity was decreased
when ROS activity was reduced (NAC, 10 mmol/L) and was augmented
when ROS activity was increased (SODNAC2). Inhibition of p38 MAPK with
pyridyl imidazole compound (SB202190, 2 to 10 µmol/L) reduced
expression of differentiation proteins occurring under basal conditions
and in response to SODNAC2. Transduction of VSMCs with an adenovirus
encoding constitutively active MKK6, an activator of p38
MAPK, increased expression of differentiation proteins, whereas
transduction with an adenovirus encoding dominant-negative p38 MAPK
decreased expression of the differentiation proteins. These findings
demonstrate that ROS can increase VSMC differentiation through a p38
MAPK–dependent pathway.
Key Words: reactive oxygen species • p38 MAPK • myosin • calponin
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