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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 \u03bcg\/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-\u03b2 (TGF-\u03b2). The results demonstrated that TGF-\u03b2 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-\u03b2, HAECs were treated with LDL for 24 h in the presence and absence of anti-TGF-\u03b2 neutralizing antibodies (anti-TGF-\u03b2 NA). The results demonstrated that the increase in CTGF induced by LDL was significantly inhibited by the anti-TGF-\u03b2 NA. To investigate the upstream mediators of TGF-\u03b2 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<jats:sup>mapk<\/jats:sup>activities did not affect LDL-induced TGF-\u03b21, CTGF, and collagen IV expression. On the other hand, SP-600125, a specific inhibitor of c-Jun NH<jats:sub>2<\/jats:sub>-terminal kinase, suppressed LDL-induced TGF-\u03b2, CTGF, and collagen IV expression, and PD-98059, a selective inhibitor of p44\/42<jats:sup>mapk<\/jats:sup>, suppressed LDL-induced TGF-\u03b2 and CTGF expression. These findings are the first to implicate the MAPK pathway and TGF-\u03b2 as key players in LDL signaling, leading to CTGF and collagen IV expression in HAECs. 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