Complement system is activated in stenotic aortic valves

Atherosclerosis. 2008 Jan;196(1):190-200. doi: 10.1016/j.atherosclerosis.2007.03.040. Epub 2007 May 10.


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 myofibroblasts 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-alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aortic Valve Stenosis / immunology*
  • Aortic Valve Stenosis / metabolism
  • Aortic Valve Stenosis / pathology
  • Cells, Cultured
  • Complement C3 / metabolism*
  • Complement C5a / metabolism*
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Humans
  • Immunohistochemistry
  • Inflammation*
  • Membrane Proteins / metabolism*
  • Receptor, Anaphylatoxin C5a
  • Receptors, Complement / metabolism*
  • Up-Regulation


  • C3 protein, human
  • C5AR1 protein, human
  • Complement C3
  • Membrane Proteins
  • Receptor, Anaphylatoxin C5a
  • Receptors, Complement
  • complement C3a receptor
  • Complement C5a