Biomedical Engineering Reference
In-Depth Information
ABSTRACT
Carbamylated LDL (cLDL), the most abundant modii ed LDL isoform in human
blood, has been recently implicated in causing atherosclerosis-prone injuries to
endothelial cells
in vitro
and atherosclerosis in patients with chronic kidney disease.
cLDL acts by inducing monocyte adhesion to endothelial cells via activation of
adhesion molecules responsible for the recruitment of monocytes. Recent data
indicate that intercellular adhesion molecule 1 (ICAM-1) in cooperation with
vascular cell adhesion molecule 1 (VCAM-1) is essential for monocyte adhesion
by cLDL-activated human vascular endothelial cells
in vitro
. Exposure of human
coronary artery endothelial cells (HCAECs) with cLDL but not native LDL
caused monocyte adhesion and the induction of ICAM-1 and VCAM-1. Silencing
of ICAM-1 by siRNA or its inhibition using neutralizing antibody resulted
in decreased monocyte adhesion to the endothelial cells. Similar silencing or
neutralizing of VCAM-1 alone did not have an ef ect but was shown to contribute
to ICAM-1 when tested simultaneously.
INTRODUCTION
Chronic kidney disease (CKD) is a common disorder that can result from a wide
variety of diseases including diabetes, hypertension and glomerulonephritis, and
that af ects about 10% of the world's population (Levey
et al.
2003). For unknown
reasons, CKD is an independent risk factor for the development of cardiovascular
disease (Sarnak
et al.
2003). At er stratii cation for age, sex, race, and the presence
or absence of diabetes, cardiovascular mortality in patients with advanced kidney
disease is 10 to 20 times that in the general population (Sarnak
et al.
2003). h e
most frequent causes of cardiovascular complications of CKD such as ischemic
heart disease, sudden death, peripheral artery diseases, arterial hypertension and
congestive heart failure are occlusive lesions due to atherosclerosis.
Monocyte (leukocyte) adhesion to activated vascular endothelial cells and
their migration into the vessel wall constitute the critical event in the initiation of
atherosclerosis. h is process is caused by the upregulation of adhesion molecules
on the surface endothelial cells and an increased expression in the vascular wall of
chemotactic factors to monocytes. Highly specii c adhesive interactions between
monocytes and endothelial cells are mediated by three main families of receptors:
members of the immunoglobulin superfamily, selectins and integrins. Recent
studies indicate that intercellular adhesion molecule 1 (ICAM-1) and vascular cell
adhesion molecule 1 (VCAM-1), members of the immunoglobulin superfamily,
are among the most common participants in monocyte attraction triggered by
cytokines, homocystein, lipopolysaccharides and other stimuli. Recent studies
demonstrated that carbamylated low-density lipoprotein (cLDL), a product of
modii cation by urea-derived cyanate, seems to be the strongest candidate for the
