Biomedical Engineering Reference
In-Depth Information
Phospholipases participate importantly in the activation of
conventional PKC
isoforms. We investigated their potential involvement in apoC-III-induced PKCα
activation. ApoC-III treatment
of THP-1 cells increased PC-PLC activity, an ef ect
that was abolished by an anti-apoC-III
antibody. A selective phosphatidylcholine-
specii c phospholipase C (PC-PLC) inhibitor inhibited apoC-III-induced PKCα
activation in a concentration-dependent manner. In addition, an inhibitor to G
αi
protein, pertussis toxin (PTX), inhibited
apoC-III-induced PKCα activation.
Taken together, these results indicated that apoC-III-containing plasma apoB
lipoproteins increase monocyte adhesion to vascular EC via PTX-sensitive G
protein and PKCα-mediated β1-integrin activation.
ApoC-III Induces VCAM-1 and ICAM-1 Activation in
Vascular EC
h e induction of adhesion molecules in vascular EC is another initiating step
in atherogenesis. Cell adhesion molecules of the immunoglobulin superfamily,
vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule
1 (ICAM-1), mediate i rm adhesion and transmigration across the vascular
endothelium of activated circulating leukocytes. We therefore examined whether
apoC-III regulates EC expression of VCAM-1 and ICAM-1 (Kawakami
et al.
2006b).
Our results showed that pre-incubation of human saphenous vein EC with
VLDL CIII+, or purii ed apoC-III, increased THP-1 cell adhesion. Incubating
resting EC with apoC-III signii cantly increased VCAM-1 protein expression
(5-fold), while moderately af ecting ICAM-1 (1.4-fold). Function-blocking
anti-VCAM-1 antibody abolished apoC-III-induced THP-1 cell adhesion to
EC, whereas ICAM-1 antibody reduced adhesion by only 30%, indicating a
predominant role of VCAM-1 in apoC-III-mediated EC activation and monocyte
adhesion. We then examined apoC-III-induced PKC activation in vascular EC.
Indeed, apoC-III treatment increased membrane-bound PKCβ in HSVEC, while
minimally af ecting PKCα activation. Treatment of vascular EC with a selective
PKCβ inhibitor abolished the increased expression of VCAM-1 by apoC-III,
indicating PKCβ's prominent role. Collectively, these results suggest that apoC-III
triggers PKCβ activation in vascular EC, which leads to the induction of VCAM-1
expression and enhanced monocyte adhesion.
ApoC-III Induces PKC-mediated NF-
k
B Activation in
Monocyte and Vascular EC
In vascular cells, PKC participates in several pro-inl ammatory and pro-atherogenic
pathways, including activation of NF-κB. NF-κB plays a pivotal role in the control
