Smooth Myocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 406

Expression of vSMC-specific genes is regulated by interactions of multiple
transcription factors that are either ubiquitous (e.g., serum response factor) or
specific of smooth myocytes (e.g., myocardin). The activity of these transcription
factors and cofactors is regulated by kinases (CamK, ERK, JNK, P38MAPK,
RoCK, 31 and PKB) [ 745 ].
Factor KLF4 represses SMC marker genes. Phosphorylation of KLF4 and its
subsequent acetylation by P300 enable SMC differentiation. Proliferative stimuli
cause KLF4 dephosphorylation and deacetylation by HDAC2, association with
ELk1, ejection of SRF, and repression of SMC markers.
Myocardin acts as a transcriptional SRF coactivator. Histone acetyltransferase
P300 is involved not only in skeletal and cardiac myogenesis, but also in SMC
differentiation. Gene activation by myocardin-SRF is enhanced upon P300 binding.
Enzyme p300 can also enhance myocardin activity independently of SRF factor.
Myocardin-related transcription factors MRTFa and MRTFb are needed in SMC
differentiation.
In fact, numerous chromatin regulators act at SMC-specific marker sites to
silence or enable access to the transcriptional machinery. Various stimuli influence
the SMC phenotype, such as transforming growth factor- β , platelet-derived growth

factor, retinoic acid, and oxidized phospholipids.
Retinoic acid that fosters SMC differentiation targets RAR re-

ceptors; protein arginine (R) methyltransferase PRMT2 bind to these receptors
and interacts nuclear receptor coactivator NCoA1, 32 another histone acetyltrans-
ferase. On the other hand, PDGFbb and oxidized phospholipids are dedifferenti-
ating stimuli that causes histone deacetylation and demethylation in SMC marker
CArG-box chromatin.
In the differentiated state, they express high concentrations of smooth
muscle-specific isoforms of contractile proteins. In the proliferative state, they
secrete large amounts of extracellular matrix components and synthesize low levels
of characteristic isoforms of contractile proteins. The biomarker smooth muscle
α

α and RXR α

-actin does not necessarily identify a smooth myocyte because it is also produced
by myofibroblasts.
Vascular smooth myocyte reprogramming results from rapid adaptation
associated with protein turnover. The ubiquitin-proteasome system participates
in rapid turnover of short- and medium-lived proteins via degradation of mediators
involved in cell signaling, 33 especially during cell differentiation and proliferation,

mono-, di-, and trimethylation either repress or stimulate transcription according to positions
of modified histone tail lysine residues. Epigenetic regulators include histone acetyltransferases,
deacetylases, and methyltransferases as well as DNA methyltransferases, among others.
31 The SRF-myocardin complex is activated by the Rho-RoCK pathway.
32 A.k.a. steroid receptor coactivator SRC1.
33 For example, both NOS2 and NOS3 isoforms are degraded by the ubiquitin-proteasome system.
Proteasome inhibition favors NOS3 dephosphorylation upon translocation from the cytosol to the
plasma membrane of ubiquitinated PP2 phosphatase. Nitric oxide hinders vSMC proliferation,
as it decreases polyubiquitination and degradation of cyclin-dependent kinase inhibitor CKI1a