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Complement system is activated in stenotic aortic valves
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DOI：10.1016/j.atherosclerosis.2007.03.040.png)
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Objective: To examine the role of the complement system, a source of powerful proinflammatory mediators, in aortic valve stenosis (AS). Methods and Results: Stenotic aortic valves (n = 24) were obtained at valve replacement surgery, and non-stenotic (n = 12) and early sclerotic (n = 4) valves at cardiac transplantations. The terminal complement complex C5b-9 was stained by immunohistochemistry. Expression of the anaphylatoxin receptors C3aR and C5aR was studied in the valves by immunohistochemistry and RT-PCR, and in isolated valve myofibroblats after stimulation with potential AS-accelerating factors (TNF-alpha and cigarette smoke) by RT-PCR. Cultured myofibroblasts were exposed to C3a, and their secretion of proinflammatory cytokines was assessed by ELISA. C5b-9 was found already in early aortic valve lesions, and its deposition was augmented in advanced stenotic valves. In stenotic valves, expression of C3aR mRNA was upregulated (p < 0.05) and strong staining of C3aR and C5aR was detected. Myofibroblasts in stenotic, but not in control valves, expressed C3aR, and, in isolated myofibroblasts, TNF-a and cigarette smoke induced C3aR mRNA expression (P < 0.05 for both). Stimulation of myofibroblasts with C3a resulted in enhanced secretion of MCP-1 (p < 0.001), IL-6 (p = 0.003), and IL-8 (p = 0.03). Conclusions: In stenotic aortic valves, complement is activated leading to generation of the anaphylatoxins C3a and C5a. Upregulation of C3aR in the valves as a result of inflammation and external risk factors, such as cigarette smoke, leads to an inflammatory response in aortic valve myofibroblasts. Complement activation in stenotic valves emerges as a novel pathogenic component of AS and may serve as a therapeutic target in this disease. (C) 2007 Elsevier Ireland Ltd. All rights reserved.
Keyword:
anaphylatoxin
aortic stenosis
complement
inflammation
valve
期刊
IF:
5.7
论文数:
2.0W
被引数:
2.5W
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