Smooth Myocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 412

MicroRNA-146a targets the 3 -untranslated region of the Kr uppel-like factor
Klf4 transcript, thereby promoting vSMC proliferation in vitro and intimal hy-
perplasiainvivo[ 754 ]. 36 Conversely, Kr uppel-like factor KLF4 binds to and
impedes activity of the miR146a promoter (mutual inhibition with feedback loop),
in competition with its KLF5 antagonist that promotes vSMC proliferation via
miR146a regulator. 37
Chronic elevation of angiotensin-2 concentration is observed in atherosclerosis
and restenosis. Angiotensin-2 causes SMC migration and proliferation, oxidative
stress, endothelial cell death, and infiltration of inflammatory cells into the arte-
rial wall, hence contributing to intimal hyperplasia. Angiotensin-2 binds to AT 1
receptor and provokes synthesis of proinflammatory cytokines such as pleiotropic
interleukin-18, chemokines, metallopeptidase MMP9, NADPH oxidase NOx1,
and superoxide [ 755 ]. Angiotensin-2 activates redox-sensitive transcription factors
NF

B and Activator protein AP1. In fact, the gene that encodes promitogenic
and promigratory interleukin-18 is targeted by both NF

κ

B and AP1 factors.
Interleukin-18 launches the production of other pro-inflammatory cytokines, che-
mokines, MMP9, and adhesion molecules. Therefore, interleukin-18 stimulates sim-
ilar promitogenic and promigratory pathways, thereby amplifying angiotensin-2-
induced, redox-dependent inflammation. Indeed, AT 1 receptor connects to NOx1 38
in smooth myocytes; angiotensin-2 enhances this association. Generation of second
messengers reactive oxygen species by NOx1 leads to activation of oxidative stress-
responsive NF

κ

B and AP1 factors. Angiotensin-2, a potent inducer of oxidative
stress at least in rat carotid artery smooth myocytes, primes IL18 production via
NOx1-ROS-mediated IKK

κ

β -RelA and JNK-Jun axes.

36 Transcription factors KLF4 and KLF5 constitute a pair of negative and positive regulators of
cell proliferation. MicroRNA-146a is upregulated upon balloon-injury as well as in oxidized low-
density lipoprotein-stimulated human macrophages.
37 In vascular smooth myocytes, KLF4 decreases miR146a production; KLF5 exerts an opposing
effect on the miR146a promoter. The KLF4-miR146a mutual inhibition includes miR146a-
mediated post-transcriptional prevention of KLF4 synthesis and KLF4-induced transcriptional
blockage of miR146a expression. Hence, KLF4 expression is regulated indirectly by KLF4 and
KLF5 through miR-146a-mediated post-transcriptional prohibition. On the other hand, KLF4
production is directly regulated by interaction of KLF4 and KLF5 with the same element on the
KLF4 promoter.
38 Among NADPH oxidase subtypes (NOx1-NOx5 and DuOx1-DuOx2), human vascular smooth
myocytes manufacture NOx1 and NOx4 isoforms. Inducible NOx1 localizes to the plasma
membrane. Constitutively active NOx4 resides in several subcellular compartments (nucleus,
endoplasmic reticulum, and mitochondria). Whereas NOx1 promotes SMC proliferation, Nox4
maintains SMC phenotype. Angiotensin-2 induces NOx1 expression in smooth myocytes, but
represses that of NOx4.