Endothelial Gene Responses to Homocysteine: Relation to Atherosclerosis

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Abstract

Chronic renal failure is associated with a 20-fold increased risk of cardiovascular mortality, in part due to accelerated atherosclerosis. Hyperhomocysteinemia (HHCy) is common in patients with chronic renal failure. It has been established that HHCy is an independent and graded risk factor for atherosclerosis, though the mechanisms responsible for it remain obscure. Using the cardiovascular cDNA microarray approach, we screened the expression of 600 cardiovascular relevant genes in human umbilical endothelial cells and identified a number of homocysteine-modulated genes. These differentially displayed genes were classified according to the functional outcome of their encoded proteins: endothelial motility cluster, signaling cluster, and lipid metabolism cluster. The results may be relevant to understanding the mechanisms underlying the pathophysiological effects of HHCy, particularly those leading to endothelial dysfunction and the pathogenesis of atherosclerosis.

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Homocysteine and cardiovascular disease.

H Refsum, P Ueland, O Nygård … (1998)

An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.

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Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis.

Christopher Heeschen, M. Johnson, Sylvia Jang … (2001)

We provide anatomic and functional evidence that nicotine induces angiogenesis. We also show that nicotine accelerates the growth of tumor and atheroma in association with increased neovascularization. Nicotine increased endothelial-cell growth and tube formation in vitro, and accelerated fibrovascular growth in vivo. In a mouse model of hind-limb ischemia, nicotine increased capillary and collateral growth, and enhanced tissue perfusion. In mouse models of lung cancer and atherosclerosis, we found that nicotine enhanced lesion growth in association with an increase in lesion vascularity. These effects of nicotine were mediated through nicotinic acetylcholine receptors at nicotine concentrations that are pathophysiologically relevant. The endothelial production of nitric oxide, prostacyclin and vascular endothelial growth factor might have a role in these effects.

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Large scale gene expression analysis of cholesterol-loaded macrophages.

J. Porter, D. Shiffman, R Somogyi … (2000)

We conducted large scale gene expression analysis of the response of macrophages to exposure to oxidized low density lipoprotein (Ox-LDL). Much of the vessel wall lesion of atherosclerosis is composed of macrophages that have become engorged with cholesterol. These resulting "foam cells" contribute to the progression of vascular disease through several pathways. As a potential model of foam cell formation, we treated THP-1 cells with 12-O-tetradecanoylphorbol 13-acetate to differentiate them into a macrophage-like phenotype and subsequently treated them with oxidized low density lipoprotein for various time periods. RNA from Ox-LDL treated and time-matched control untreated cells was hybridized to microarrays containing 9808 human genes. 268 genes were found to be at least 2-fold regulated at one or more time points. These regulation patterns were classified into seven clusters of expression profiles. The data is discussed in terms of the overall pattern of gene expression, the thematic classification of the responding genes, and the clustering of functional groups in distinct expression patterns. The magnitude and the temporal patterns of gene expression identified known and novel molecular components of the cellular response that are implicated in the growth, survival, migratory, inflammatory, and matrix remodeling activity of vessel wall macrophages. In particular, the role of nuclear receptors in mediating the gene expression modulation by Ox-LDL is highlighted.

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Author and article information

Journal

Journal ID (publisher-id): EXN

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISBN: 978-3-8055-7383-2

ISBN: 978-3-318-00822-7

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2002

Publication date (Print): 2002

Publication date (Electronic): 05 April 2002

Volume: 10

Issue: 2

Pages: 164-169

Affiliations

Departments of ^aPhysiology and Biophysics and ^bMedicine, State University of New York, Stony Brook, N.Y., USA

Article

Publisher ID: 49911 Other ID: Exp Nephrol 2002;10:164–169

DOI: 10.1159/000049911

PubMed ID: 11937763

SO-VID: 2c865946-bd10-477e-87c1-8599a3c94f3c

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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Endothelial Gene Responses to Homocysteine: Relation to Atherosclerosis

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Abstract

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Karger: Nephrology

Most cited references 5

Homocysteine and cardiovascular disease.

Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis.

Large scale gene expression analysis of cholesterol-loaded macrophages.

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