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(Circulation Research. 2001;89:1155.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Transforming Growth Factor-ß₁ Modulates Oxidatively Modified LDL–Induced Expression of Adhesion Molecules

Role of LOX-1

Hongjiang Chen, Dayuan Li, Tom Saldeen, Jawahar L. Mehta

From the Departments of Internal Medicine and Physiology (H.C., D.L., J.L.M.), University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; and the Department of Surgical Sciences (T.S.), University of Uppsala, Sweden.

Correspondence to Jawahar L. Mehta, MD, PhD, Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, 4301 West Markham, Mail Slot 532, Little Rock, AR 72205-7199. E-mail MehtaJL{at}uams.edu

Oxidatively modified LDL (ox-LDL) activates a lectin-like receptor, LOX-1, which results in the expression of adhesion molecules on endothelial surface. We investigated the regulation of the expression of transforming growth factor-ß₁ (TGF-ß₁) and its receptors by ox-LDL and the functional significance of this interaction with regard to adhesion molecule expression in human coronary artery endothelial cells (HCAECs). Ox-LDL, in a time- and concentration-dependent manner, upregulated the expression of all 3 subtypes (1, 2, and 3 [including endoglin]) of TGF-ß₁ receptors and decreased active TGF-ß₁ synthesis (all P<0.05 versus control and native-LDL–treated cells). Treatment of HCAECs with a monoclonal antibody to LOX-1 attenuated ox-LDL–mediated upregulation of TGF-ß₁ receptors and decrease in TGF-ß₁ synthesis (P<0.05 versus ox-LDL alone). Ox-LDL also enhanced the expression of P-selectin and ICAM-1 as well as monocyte adhesion to HCAECs (P<0.05 versus control untreated cells). Pretreatment with recombinant TGF-ß₁ attenuated the enhanced expression of adhesion molecules and monocyte adhesion to HCAECs (P<0.05 versus ox-LDL alone). Effects of recombinant TGF-ß₁ were blocked by antibody to TGF-ß₁ receptor type 2, but not by antibody to endoglin. Thus ox-LDL, via activation of LOX-1, increases the expression of TGF-ß₁ receptors and decreases TGF-ß₁ synthesis in HCAECs. Recombinant TGF-ß₁, by binding to TGF-ß₁ type 2 receptors, modulates ox-LDL–mediated expression of adhesion molecules and monocyte adhesion to HCAECs.

Key Words: adhesion molecules • endothelial cells • oxidatively modified LDL • transforming growth factor-ß₁

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