Regulation of Endothelial Activation and Vascular Inflammation by Shear Stress - Bioanalysis Advanced Materials Methods and Devices - page 80

endothelial cells. For instance, MKP-1 is over expressed in regions of vascular
endothelium subject to laminar unidirectional high shear stress. These regions are
termed atheroprotective regions as they do not exhibit any signs of developing
atherosclerosis. The consequence of MKP-1 expression by these endothelial cells is
that it negatively regulates the JNK and p38 pathways and thus hampers inflamma-
tion [ 36 ]. On the other hand, it also suppresses VCAM-1 expression [ 36 ] which
promotes the recruitment of leukocytes to the vessel walls. Thus, high shear stress
can prove to be atheroprotective in that it protects arteries from induction of
persistent endothelial expression of MKP-1, which in turn, suppresses the activities
of p38 and JNK [ 36 ]. Prior studies revealed that MKP-1 exerts anti-inflammatory
effects in EC by inhibiting the expression of adhesion molecules and chemokines
[ 5 , 31 , 36 ]. MKP-1 also suppresses the activation of macrophages and their capacity
to produce the pro-atherogenic cytokine TNF

[ 7 ]. In addition, MKP-1 can be
induced by low density lipoprotein (LDL) [ 19 ] and cyclic strain in smooth muscle
cells [ 16 ] and reduces their proliferation. Thus, MKP-1 may exert anti-atherogenic
effects in vascular endothelium by suppressing EC activation and also influence
lesion development by regulating macrophage physiology and smooth muscle cell
accumulation. Hence more research has to be carried out with respect to MKP-1
expression in regions that are susceptible to low, oscillatory shear stress and
exploitation of this expression to yield therapeutic benefits.

a

6.2.2 Nuclear Factor Erythroid 2-Related Factor 2

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a member of the “cap 'n' collar”
family of basic leucine zipper transcription factors that is important in protecting
cells against oxidative damage by reactive oxygen species (ROS) [ 3 ]. Nrf2 plays an
important role in the protection of endothelial cells via antioxidant response
element (ARE)-mediated gene expression of phase II detoxification antioxidant
proteins. Both types of shear stress, laminar and oscillatory, have shown to increase
the expression of Nrf2. However, stabilization of Nrf2 and expression of genes
modulated by Nrf2 is only induced by laminar shear stress. In studies on human
umbilical vein endothelial cells (HUVEC), induction of Nrf-2 regulated genes such
as heme oxygenase 1, NAD(P)H quinone oxidoreductase1, glutamate-cysteine
ligase modifier subunit, and ferritin heavy chain is carried out by laminar shear
stress [ 32 , 33 ]. The regulation of these genes is inhibited when treated with Nrf2
siRNA. Laminar shear stress has been observed to induce gene expression of
cytoprotective enzymes for glutathione biosynthesis and detoxification which are
regulated by Nrf2. Laminar shear stress might activate Nrf2 via a phosphoinositol
3-kinase/Akt-dependent signalling pathway [ 10 ].
Following activation by laminar shear stress, Nrf2 acts in an anti-inflammatory
manner similar to that of MKP-1. Nrf2 is constitutively active in endothelial cells
in atheroprotected regions and has been observed to reduce the proinflammatory
activities of p38 MAP kinase by inactivating it [ 35 ]. Nrf2 also suppresses the