(Circulation. 2001;103:2717.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Homocysteine Induces Expression and Secretion of Monocyte Chemoattractant Protein-1 and Interleukin-8 in Human Aortic Endothelial Cells
Implications for Vascular Disease
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997, and at the Second International Conference on Homocysteine Metabolism, Nijmegen, the Netherlands, April 26–29, 1998, and published in abstract form (Circulation. 1997;96:I-286) (Neth J Med. 1998;52[suppl]:S1).
From the Departments of Cell Biology (R.P., P.M.D., D.W.J.) and Molecular Cardiology (N.S.), Lerner Research Institute, and Department of Cardiology, Cleveland Clinic Foundation (K.R.), Cleveland, Ohio. Dr Poddar is now at the Department of Genetics, Yale University School of Medicine, New Haven, Conn; Dr Sivasubramanian is now at the Winters Center for Heart Failure Research, Section of Cardiology, Department of Medicine, Baylor College of Medicine, Veterans Affairs Medical Center, Houston, Tex; Dr Robinson is now at the Department of Cardiology, Wake Forest University, Baptist Medical Center, Winston Salem, NC.
Correspondence to Donald W. Jacobsen, PhD, Department of Cell Biology, NC10, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail jacobsd{at}ccf.org
Background—Proinflammatory cytokines play key roles in atherogenesis and disease progression. Because hyperhomocysteinemia is an independent risk factor for cardiovascular disease, we hypothesized that homocysteine could be atherogenic by altering the expression of specific cytokines in vascular endothelial cells.
Methods and
Results—Northern blot and RNase protection
assays showed that
DL-homocysteine induced
mRNA expression of the proinflammatory cytokines monocyte
chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in cultured
human aortic endothelial cells (HAECs). Homocysteine
had no effect on expression of other cytokines, namely tumor
necrosis factor-
, granulocyte-macrophage colony–stimulating
factor, interleukin-1ß, and transforming growth factor-ß. MCP-1
mRNA expression increased 1 hour after homocysteine treatment, reached
a maximum within 2 to 4 hours, and declined to basal levels over the
next 24 hours. Induction of mRNA expression for both chemokines was
observed with as little as 10 µmol/L
DL-homocysteine, and
maximal expression was achieved with 50 µmol/L
DL-homocysteine.
Homocysteine also triggered the release of MCP-1 and IL-8 protein from
HAECs into the culture medium. The induction was specific for
homocysteine, because equimolar concentrations of
L-homocystine,
L-cysteine, and
L-methionine had no effect
on mRNA levels and protein release. Furthermore,
L-homocysteine induced
chemokine expression, but
D-homocysteine did not,
thus demonstrating enantiomeric specificity. The culture medium from
homocysteine-treated HAECs promoted chemotaxis in human
peripheral blood monocytes and U937 cells. Anti–human
recombinant MCP-1 antibody blocked the
migration.
Conclusions—Pathophysiological levels of L-homocysteine alter endothelial cell function by upregulating MCP-1 and IL-8 expression and secretion. This suggests that L-homocysteine may contribute to the initiation and progression of vascular disease by promoting leukocyte recruitment.
Key Words: homocysteine • peptides • endothelium • cells • cardiovascular diseases
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