Pilz, Renate B

Schwappacher, Raphaela

Zhang, Tong

Zhuang, Shunhui

BMC Pharmacology

English

PubMed

Tong Zhang

Raphaela Schwappacher

Shunhui Zhuang

Renate B Pilz

Springer - Publisher Connector

BioMed CentralBMC Pharmacology
ssOpen AccePoster presentation
Regulation of smooth muscle-specific gene expression by 
cGMP-dependent protein kinase
Tong Zhang, Raphaela Schwappacher, Shunhui Zhuang and Renate B Pilz*
Address: Department of Medicine University of California, San Diego, La Jolla, CA 92093, USA
Email: Renate B Pilz* - rpilz@ucsd.edu
* Corresponding author    
Background
Vascular smooth muscle cells (VSMCs) in normal adult
blood vessels exhibit a differentiated, "contractile" pheno-
type, but in atherosclerotic disease and after acute vascular
injury, they de-differentiate into a proliferative, "syn-
thetic" phenotype; the latter is characterized by decreased
smooth muscle (SM)-specific gene expression and
decreased cGMP-dependent protein kinase (PKG) activity
[1,2]. Prolonged in vitro culture of primary aortic VSMCs,
or exposure of pulmonary VSMCs to hypoxia also leads to
de-differentiation associated with loss of PKG, and restor-
ing PKG activity increases SM-specific gene expression and
re-differentiates cells into the contractile phenotype, but
the mechanism(s) whereby PKG regulates SM genes are
poorly understood [2,3].
Results
Using siRNA-mediated down-regulation or pharmaco-
logic inhibition of PKG, we recently showed that PKG is
necessary for maintaining high SM-specific gene expres-
sion in differentiated VSMCs, and that PKG stimulation of
SM-specific promoters requires serum response factor
(SRF), the SM-specific transcription factor GATA-6, and
the cysteine-rich LIM-only protein CRP4. Like other CRP-
family proteins, CRP-4 appears to act an adaptor protein,
promoting the cooperation between SRF and GATA pro-
teins on SM-specific promoters; PKG associates with CRP4
and phosphorylates the protein in intact cells. Phosphor-
ylation-deficient, or PKG binding-deficient CRP4 mutants
did not support cGMP/PKG stimulation of the SM-∀-actin
promoter. cGMP/PKG enhanced SRF binding to a SM-∀-
actin promoter CArG element in the presence of wild type,
but not mutant CRP4. Chromatin immunoprecipitation
assays showed that CRP4, SRF, and PKG associate with the
CArG elements of endogenous SM-specific genes in intact
cells. In the presence of CRP4, cGMP/PKG increased SRF-
and GATA6-dependent expression of endogenous SM-
specific genes in pluripotent embryonal 10T1/2 cells.
Platelet-derived growth factor-BB (PDGF) is a key regula-
tor of VSMC phenotypic modulation, and potently sup-
presses SM-specific gene transcription (1). We found that
PDGF suppressed PKG expression in VSMCs, and that
restoring PKG reversed PDGF inhibition of SM-specific
genes without affecting PDGF activation of extracellular
signal-regulated kinases (Erk-1/2) or phosphatidyl-inosi-
tol-3-kinase/Akt pathways. PDGF treatment or siRNA-
mediated down-regulation of PKG induced dissociation
of SRF and CRP4 from SM-specific promoters, and PKG
re-expression appeared to prevent these effects.
Conclusion
We conclude that PKG maintains SM-specific gene expres-
sion in differentiated VSMCs and prevents PDGF-induced
down-regulation of SM-specific genes by facilitating
assembly of CRP4/SRF complexes at SM-specific promot-
ers; PKG modulates the adaptor function of CRP4 by
phosphorylating CRP4, and may affect recruitment of SRF
co-factors.
from 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications
Regensburg, Germany. 19–21 June 2009
Published: 11 August 2009
BMC Pharmacology 2009, 9(Suppl 1):P79 doi:10.1186/1471-2210-9-S1-P79
<supplement> <title> <p>4th International Conference of cGMP Generators, Effectors and Therapeutic Implications</p> </title> <note>Meeting abstracts – A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1471-2210-9-S1-full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/1471-2210-9-S1-info.pdf</url> </supplement>
This abstract is available from: http://www.biomedcentral.com/1471-2210/9/S1/P79
© 2009 Zhang et al; licensee BioMed Central Ltd. Page 1 of 2
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References
1. Owens GK, Kumar MS, Wamhoff BR: Molecular regulation of
vascular smooth muscle cell differentiation in development
and disease.  Physiol Rev 2004, 84:767-801.
2. Lincoln TM, Wu X, Sellak H, Dey N, Choi CS: Regulation of vascu-
lar smooth muscle cell phenotype by cyclic GMP and cyclic
GMP-dependent protein kinase.  Front Biosci 2006, 11:356-67.
3. Zhou W, Dasgupta C, Negash S, Raj JU: Modulation of pulmonary
vascular smooth muscle cell phenotype in hypoxia: role of
cGMP dependent protein kinase.  Am J Physiol Lung Cell Mol Physiol
2007, 292:L1459-66.Page 2 of 2
(page number not for citation purposes)


Regulation of smooth muscle-specific gene expression by cGMP-dependent protein kinase

Crossref

BR: Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev

CS: Regulation of vascular smooth muscle cell phenotype by cyclic GMP and cyclic GMP-dependent protein kinase. Front Biosci

Modulation of pulmonary vascular smooth muscle cell phenotype in hypoxia: role of cGMP dependent protein kinase. Am J Physiol Lung Cell Mol Physiol

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Regulation of smooth muscle-specific gene expression by cGMP-dependent protein kinase

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