Vascular Biology – Hemodynamics – Hypertension
Kidney International (2005) 68, 173–178; doi:10.1111/j.1523-1755.2005.00391.x
Carbamylated low-density lipoprotein induces death of endothelial cells: A link to atherosclerosis in patients with kidney disease
ERCAN OK, ALEXEI G BASNAKIAN, EUGENE O APOSTOLOV, YOUSRI M BARRI and SUDHIR V SHAH
University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
Correspondence: Sudhir V. Shah, University of Arkansas for Medical Sciences, Department of Internal Medicine, Division of Nephrology, 4301 W. Markham St., Slot 501, Little Rock, AR 72205. E-mail: shahsudhirv@uams.edu
Received 12 October 2004; Revised 14 December 2004; Accepted 27 January 2005.
Abstract
Carbamylated low-density lipoprotein induces death of endothelial cells: A link to atherosclerosis in patients with kidney disease.
Background
The presence of accelerated atherosclerosis in patients with kidney disease cannot be entirely explained by traditional cardiovascular risk factors. Exposure to urea, which is normally present in human blood plasma and elevated in patients with kidney disease, leads to the carbamylation of proteins. We postulated that low-density lipoprotein (LDL) carbamylated by urea has biologic effects relevant to atherosclerosis.
Methods
To produce carbamylated LDL (cLDL), human native LDL (nLDL) was chemically modified in vitro by exposure to potassium cyanate. Human coronary artery endothelial cells (HCAECs) and human coronary artery smooth muscle cells (CASMCs) were treated in vitro with cLDL or nLDL. Irreversible cell death was measured using the lactate dehydrogenase (LDH) assay, apoptosis was assessed by annexin V binding, and proliferation was determined using bromodeoxyuridine (BrdU) incorporation. Total plasma protein carbamylation and plasma cLDL were measured in hemodialysis patients using the homocitrulline assay and enzyme-linked immunosorbent assay (ELISA).
Results
Our studies demonstrated that cLDL but not nLDL induced dose-dependent vascular cell injuries relevant to atherosclerosis, which included the proliferation of vascular smooth muscle cells and endothelial cell death. Under light microscopy, endothelial cells treated with cLDL showed signs of morphologic alterations. The injury to endothelial cells measured by LDH release was time-dependent and correlated with the degree of LDL carbamylation. At least a part of the endothelial cell population treated with cLDL died by apoptosis. In patients with advanced renal disease on hemodialysis, total plasma protein carbamylation and plasma cLDL were several times higher than in control healthy individuals.
Conclusion
Collectively these data suggest the potential role of carbamylated LDL in accelerated atherosclerosis in patients with chronic renal disease and, possibly, in healthy individuals.
Keywords:
low-density lipoprotein, carbamylation, carbamylated LDL, kidney, end-stage renal disease, endothelial cells
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