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This Article Full Text Full Text (PDF) All Versions of this Article: 290/4/H1624    most recent 01233.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Sohn, M. Articles by Jaffa, A. A. Search for Related Content PubMed PubMed Citation Articles by Sohn, M. Articles by Jaffa, A. A.

Mechanisms of low-density lipoprotein-induced expression of connective tissue growth factor in human aortic endothelial cells

Divisions of ¹Endocrinology, Diabetes, and Medical Genetics and of ²Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, and ³The Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina

Submitted 7 December 2004 ; accepted in final form 1 November 2005

Hyperlipidemia is a recognized risk factor for atherosclerotic vascular disease. The underlying mechanisms that link lipoproteins and vascular disease are undefined. Connective tissue growth factor (CTGF) is emerging as a key determinant of progressive fibrotic diseases, and its expression is upregulated by diabetes. To define the mechanisms through which low-density lipoproteins (LDL) promote vascular injury, we evaluated whether LDL can modulate the expression of CTGF and collagen IV in human aortic endothelial cells (HAECs). Treatment of HAECs with LDL (50 µg/ml) for 24 h produced a significant increase in the mRNA and the protein levels of CTGF and collagen IV compared with unstimulated controls. To explore the mechanisms by which LDL regulates CTGF and collagen IV expression in HAECs, we determined first if CTGF and collagen IV are downstream targets for regulation by transforming growth factor- (TGF-). The results demonstrated that TGF- produced a concentration-dependent increase in the protein levels of CTGF. To assess whether the induction of CTGF in response to LDL is mediated via autocrine activation of TGF-, HAECs were treated with LDL for 24 h in the presence and absence of anti-TGF- neutralizing antibodies (anti-TGF- NA). The results demonstrated that the increase in CTGF induced by LDL was significantly inhibited by the anti-TGF- NA. To investigate the upstream mediators of TGF- on activity of CTGF in response to LDL, HAECs were treated with LDL for 24 h in the presence and absence of cell-permeable MAPK inhibitors. Inhibition of p38^mapk activities did not affect LDL-induced TGF-1, CTGF, and collagen IV expression. On the other hand, SP-600125, a specific inhibitor of c-Jun NH₂-terminal kinase, suppressed LDL-induced TGF-, CTGF, and collagen IV expression, and PD-98059, a selective inhibitor of p44/42^mapk, suppressed LDL-induced TGF- and CTGF expression. These findings are the first to implicate the MAPK pathway and TGF- as key players in LDL signaling, leading to CTGF and collagen IV expression in HAECs. The data also point to a potential mechanistic pathway through which lipoproteins may promote vascular injury.

transforming growth factor-; mitogen-activated protein kinase; collagen IV