Biomedical Engineering Reference
In-Depth Information
transcription factors that cause the inl ammation process (Chung
et al.
2006, 2009).
It is likely that an oxidative stress-induced redox imbalance and a dysregulated
immune system with age increase the systemic inl ammatory status to activate a
wide variety of inl ammatory mediators, including AMs. h e salient point is that
unresolved, chronic inl ammation during aging may act as the pathophysiological
link that drives normal functional changes to become many of the age-related
degenerative diseases (Chung
et al.
2009).
ALTERED AMs BY AGE-RELATED REDOX MEDIATORS
AMs are well known to mediate interactions between blood cells (leukocyte, platelet)
and ECs. h e coordinated recruitment of leukocytes to sites of inl ammation is
largely governed by the time-course and magnitude of endothelial AM expression.
h e expression of AMs during inl ammation is generally transient and quick, but a
prolonged and dysregulated AM-mediated process of leukocyte recruitment ot en
results in EC dysfunction.
It is well established that most of the regulations of inl ammatory AMs in
cells are at the transcriptional level. AMs are stimulated when cells are exposed
to mediators such as the pro-inl ammatory cytokines, TNF-α and IL-1β. Two
transcription factors, NF-kappaB and AP-1, are identii ed as major regulators
responsible for the upregulation of E-selectin, P-selectin, VCAM-1 and ICAM-1
on cytokine-treated ECs.
In addition to typical cytokine stimuli, various other AM regulators have
been identii ed
(Fig. 1)
and most of these regulators are inl uenced by age-
related oxidative stress. For instance, many studies have indicated that oxidized
low-density lipoprotein (oxLDL) is an ef ective stimulus for the expression of
AMs on ECs. Our recent study reported that the major components of oxLDL,
lysophosphatidylcholine (LPC) directly induce the endothelial expression of
VCAM-1 and P-selectin through a G-protein coupled receptor 4 pathway (Zou
et al.
2007). It was shown that advanced glycation end products (AGEs) enhanced
levels of mRNA and antigen for VCAM-1, ICAM-1, and E-selectin in primary
cultures of human saphenous vein ECs through engagement of AGE receptor,
thereby increasing adhesion of polymorphonuclear leukocytes to stimulated ECs.
Age-related oxidative stress is reported to play an important role in the
upregulation of inl ammatory AMs. Oxidative stress induced by either depletion
of glutathione or generation of reactive species (RS) induced the
upregulation of
P-selectin and VCAM-1 in ECs. NADPH oxidase-derived RS induce expression
of VCAM-1 and ICAM-1 in ECs (Dworakowski
et al.
2008). Expressions of both
P-selectin and VCAM-1 were induced in a dose
dependent manner by XOD/
xanthine, which generates
•
O
2
-
and H
2
O
2
, indicating
the role of reactive oxygen
species in triggering AM expression (Zou
et al.
2006).
Among several stimuli we
tested using the VCAM-1 reporter vector, LPC, TNF-α and IL-1β were highly
