Objective-We investigated the comparative roles of mitogen-activated protein (MAP) kinases, including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38, in vascular smooth muscle cell (VSMC) proliferation, migration, and gene expression. Methods and Results-VSMCs were infected with recombinant adenovirus containing dominant-negative mutants of ERK, p38, and JNK (Ad-DN-ERK, Ad-DN-p38, and Ad-DN-JNK, respectively) to specifically inhibit the respective MAP kinases and then stimulated with platelet-derived growth factor (PDGF)-BB. Ad-DN-ERK attenuated PDGF-BB-induced VSMC proliferation more potently than Ad-DN-p38 or Ad-DN-JNK, indicating the dominant role of ERK in VSMC proliferation. Ad-DN-ERK, Ad-DN-p38, and Ad-DN-JNK similarly inhibited PDGF-induced VSMC migration. Ad-DN-ERK and Ad-DN-JNK suppressed PDGF-BB-induced downregulation of cyclin-dependent kinase inhibitor p27 Kip1 , whereas Ad-DN-p38 decreased PDGF-BB-induced upregulation of p21 Cip1 . Ad-DN-ERK inhibited PDGF-BB-induced plasminogen activator inhibitor type-1 (PAI-1), monocyte chemoattractant protein-1, and transforming growth factor- 1 expressions, Ad-DN-p38 blocked monocyte chemoattractant protein-1 and transforming growth factor- 1 expression but not PAI-1, whereas Ad-DN-JNK suppressed only PAI-1 expression. Moreover, in vivo gene transfer of Ad-DN-p38 to rat carotid artery caused the inhibition of intimal hyperplasia by balloon injury, indicating the involvement of p38 in vascular remodeling in vivo. Key Words: platelet-derived growth factor Ⅲ gene transfer Ⅲ vascular smooth muscle cell Ⅲ proliferation Ⅲ gene expression P latelet-derived growth factor-BB (PDGF-BB) is one of the most potent mitogens and chemoattractants for vascular smooth muscle cells (SMCs) and plays the central role in the onset and development of various vascular disorders. [1][2][3][4][5][6] As reviewed, 7,8 PDGF-BB, through interaction with PDGF, activates multiple signaling pathways in vascular SMCs, including SHP-2, Src, PLC-␥, Ras, protein kinase A, phosphatidylinositol 3-kinase (PI3-kinase), and mitogen-activated protein (MAP) kinases, which are supposed to play some role in PDGF-induced cellular responses. Ras, 9 Src, 10 and c-Jun 11 contribute to PDGFinduced vascular SMC proliferation. On the other hand, PI 3-kinase is known to participate in PDGF-induced vascular SMC migration. 12 However, the molecular mechanism of vascular SMC proliferation and migration by PDGF-BB remains to be fully understood. PDGF-BB not only stimulates proliferation and migration in vascular SMCs but also induces various genes. Interestingly, previous reports indicate that PDGF-BB induces plasminogen activator inhibitor type-1 (PAI-1), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor- 1 (TGF- 1 ) in vascular SMCs. [13][14][15] Increased PAI-1 that leads to inhibition of plasminogen activation impairs fibrinolysis and thereby promotes thrombosis. 16 MCP-1 is the major chemotactic factor involved in the migration of monocytes into...
Ang II is a central mediator of vascular inflammation and remodeling. The transcription factor Ets-1 is rapidly induced in vascular smooth muscle and endothelial cells of the mouse thoracic aorta in response to systemic Ang II infusion. Arterial wall thickening, perivascular fibrosis, and cardiac hypertrophy are significantly diminished in Ets1 -/-mice compared with control mice in response to Ang II. The induction of 2 known targets of Ets-1, cyclin-dependent kinase inhibitor p21 CIP and plasminogen activator inhibitor-1 (PAI-1), by Ang II is markedly blunted in the aorta of Ets1 -/-mice compared with wild-type controls. Expression of p21 CIP in VSMCs leads to cellular hypertrophy, whereas expression of p21 CIP in endothelial cells is associated with cell cycle arrest, apoptosis, and endothelial dysfunction. PAI-1 promotes the development of perivascular fibrosis. We have identified monocyte chemoattractant protein-1 (MCP-1) as a novel target for Ets-1. Expression of MCP-1 is similarly reduced in Ets1 -/-mice compared with control mice in response to Ang II, which results in significantly diminished recruitment of T cells and macrophages to the vessel wall. In summary, our results support a critical role for Ets-1 as a transcriptional mediator of vascular inflammation and remodeling in response to Ang II.
ERG (Ets Related Gene) is an ETS transcription factor that has recently been shown to regulate a number of endothelial cell (EC) restricted genes including VE-cadherin, von Willebrand Factor (vWF), endoglin, and intercellular adhesion molecule-2 (ICAM-2). Our preliminary data demonstrate that unlike other ETS factors, ERG exhibits a highly EC-restricted pattern of expression in cultured primary cells and several adult mouse tissues including the heart, lung, and brain. In response to inflammatory stimuli, such as TNF-α, we observed a marked reduction of ERG expression in EC. To further define the role of ERG in the regulation of normal EC function we used RNA interference to knockdown ERG. Microarray analysis of RNA derived from ERG siRNA- or TNF-α–treated HUVEC revealed significant overlap (P value <0.01) in the genes that are up- or downregulated. Of particular interest to us was a significant change in expression of interleukin-8 (IL-8) at both protein and RNA levels. Exposure of EC to TNF-α is known to be associated with increased neutrophil attachment. We observed that knockdown of ERG in HUVEC is similarly associated with increased neutrophil attachment compared to control siRNA-treated cells. This enhanced adhesion could be blocked with IL-8 neutralizing or IL-8 receptor blocking antibodies. ERG can inhibit the activity of the IL-8 promoter in a dose dependent manner. Direct binding of ERG to the IL-8 promoter in EC was confirmed by chromatin immunoprecipitation. In summary, our findings support a role for ERG in promoting anti-inflammatory effects in EC through repression of inflammatory genes such as IL-8.
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