Regulation of Endothelial Activation and Vascular Inflammation by Shear Stress - Bioanalysis Advanced Materials Methods and Devices - page 81

VCAM-1 expression. The other manner in which Nrf2 controls endothelial acti-
vation is by reducing MKK3/6 signaling to p38 and by enhancing the activity of
MKP-1. The mechanism behind the MKK3/6 suppression by Nrf2 is likely to
involve redox regulation too because ASK1, a MAP kinase that acts upstream
from MKK3/6, is known to be inhibited by reduced forms of glutathione and
thioredoxin [ 35 ]. Further evidence suggests that Nrf2 can enhance the catalytic
activity of MKP-1 by promoting a reducing environment via the induction of
multiple antioxidants. Thus, it is proposed that laminar shear stress suppresses
endothelial cell activation at atheroprotected sites by inducing MKP-1 and by
simultaneously enhancing MKP-1 activity via activation of Nrf2 [ 35 ].
Interestingly, in regions of low shear stress that are more susceptible to athero-
sclerosis, Nrf2 seems to be expressed in a nonactive form and is incapable of
suppressing the pro-inflammatory milieu that follows the formation of atherogenic
lesions [ 35 ]. In addition to these observations, HUVEC challenged with laminar
shear stress and simultaneously treated with Nrf2 siRNA (that will interefere with
the expression of biologically active Nrf2) showed an upregulation of expression of
adhesion molecules and chemokines (Takabe et al. 2011). In the same study,
arterial endothelial cells isolated from Nrf2 deficient mice also demonstrated a
similar result. The collective observation from the above studies suggest that Nrf2
might be an important therapeutic candidate to suppress inflammation in the
vascular endothelium, as it can inhibit expression of adhesion molecules and
recruitment of chemokines.

6.2.3 Kruppel-like Factor

Kruppel-like factor (KLF2) is an endothelial transcription factor, the expression
of which is specifically induced by laminar shear stress [ 21 ]. It is an anti-
inflammatory transcription factor that aids in maintaining the atheroprotective
phenotype of vascular endothelial cells. KLF2 induces the expression of
atheroprotective endothelial nitric oxide (eNOS) and thrombomodulin whilst
downregulating the expression of pro-atherogenic MCP-1 and endothelin [ 11 ].
KLF2 also inhibits the expression of VCAM-1 and E-selectin, and thus, it
suppresses the initiation of the inflammatory cascade that precedes the rolling
and adhesion of inflammatory cells [ 27 ].

6.2.4 JNK-NF- k B Pathway

The nuclear factor B) family of

transcription factors regulates vascular inflammation by inducing adhesion proteins
and other proinflammatory molecules in vascular endothelial cells [ 30 ]. There are
five different subunit forms of NF-

-light-chain-enhancer of activated B cells (NF-

k k

B and the RelA/p50 heterodimer is the most

k