Complement system is activated in stenotic aortic valves.
OBJECTIVE
To examine the role of the complement system, a source of powerful proinflammatory mediators, in aortic valve stenosis (AS).


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.
Helske
Satu
S
Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland.
Oksjoki
Riina
R
Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland.
Lindstedt
Ken A
KA
Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland.
Lommi
Jyri
J
Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
Turto
Heikki
H
Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
Werkkala
Kalervo
K
Division of Cardiothoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland.
Kupari
Markku
M
Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
Kovanen
Petri T
PT
Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland. Electronic address: petri.kovanen@wri.fi.
D001024:Aortic Valve Stenosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003176:Complement C3 / Q000378:metabolism*; D015936:Complement C5a / Q000378:metabolism*; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008565:Membrane Proteins / Q000378:metabolism*; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000378:metabolism*; D015854:Up-Regulation
C038245:C3 protein, human; C488033:C5AR1 protein, human; D003176:Complement C3; D008565:Membrane Proteins; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C085567:complement C3a receptor; D015936:Complement C5a