- 作者：Satu Helske ; Riina Oksjoki ; Ken A. Lindstedt ; Jyri Lommi ; Heikki Turto ; Kalervo Werkkala ; Markku Kupari ; Petri T. Kovanen
- 关键词：Anaphylatoxin ; Aortic stenosis ; Complement ; Inflammation ; Valve
- 刊名：Atherosclerosis
- 出版年：2008
- 出版时间：January 2008
- 年：2008
- 卷：196
- 期：1
- 页码：190-200
- 全文大小：1656 K
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-α 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-α 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.