NADPH Oxidases Regulate CD44 and Hyaluronic Acid Expression in Thrombin-treated Vascular Smooth Muscle Cells and in Atherosclerosis
| Autor: | Aleksandr E. Vendrov, Nageswara R. Madamanchi, Marschall S. Runge, Cedric Szyndralewiez, Patrick Page, Kimberly C. Molnar, Xi Lin Niu, Mason Runge |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Vascular smooth muscle
Myocytes Smooth Muscle In Vitro Techniques Hyaluronan Synthase 2 Biochemistry Muscle Smooth Vascular Mice Thrombin medicine Animals Hyaluronic Acid Molecular Biology Aorta Mice Knockout Regulation of gene expression NADPH oxidase biology NADPH Oxidases Cell Biology Atherosclerosis Molecular biology AP-1 transcription factor Hyaluronan Receptors Gene Expression Regulation NOX1 cardiovascular system biology.protein Signal transduction Reactive Oxygen Species Signal Transduction medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 285:26545-26557 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110.143917 |
| Popis: | The intracellular signaling events by which NADPH oxidase-generated reactive oxygen species (ROS) modulate vascular smooth muscle cell (VSMC) function and atherogenesis are yet to be entirely elucidated. We previously demonstrated that NADPH oxidase deficiency decreased atherosclerosis in apoE(-/-) mice and identified adhesion protein CD44 as an important ROS-sensitive gene expressed in VSMC and atherosclerotic lesions. Here, we examined the molecular mechanisms by which NADPH oxidase-generated ROS regulate the expression of CD44 and its principal ligand, hyaluronan (HA), and how CD44-HA interaction affects VSMC proliferation and migration and inflammatory gene expression in apoE(-/-) mice aortas. Thrombin-induced CD44 expression is mediated by transcription factor AP-1 in a NADPH oxidase-dependent manner. NADPH oxidase-mediated ROS generation enhanced thrombin-induced HA synthesis, and hyaluronan synthase 2 expression in VSMC. Hyaluronidase, which generates low molecular weight HA (LMW-HA), is induced in VSMC in a NADPH oxidase-dependent manner and LMW-HA stimulated ROS generation and cell proliferation in wild-type but not p47(phox-/-) VSMC, effects that were enhanced by thrombin pretreatment. Haptotactic VSMC migration toward HA was increased by thrombin in a CD44-dependent manner. HA expression in atherosclerotic lesions and plasma-soluble CD44 and HA levels were higher in apoE(-/-) compared with apoE(-/-)/p47(phox-/-) mice. HA-regulated pro-inflammatory gene expression was higher in apoE(-/-) than apoE(-/-)/p47(phox-/-) mouse aortas. GKT136901, a specific inhibitor of Nox1- and Nox4-containing NADPH oxidase activity, attenuated ROS generation and atherosclerosis and decreased CD44 and HA expression in atherosclerotic lesions. Together, these data suggest that increased CD44 and HA expression and CD44-HA-dependent gene regulation may play a role in atherosclerosis stimulated by NADPH oxidase activation. |
| Databáze: | OpenAIRE |
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