Organ culture as a tool to identify early mechanisms of serotonergic valve disease.
OBJECTIVE
Although the late effects of serotonergic valve disease are known, the early mechanisms of the characteristic plaque formation are poorly understood.


METHODS
To model conditions leading to plaque formation on mitral valves, samples (n = 6-8 per treatment) cultured in a splashing bioreactor were exposed to serotonin (5HT) and norfenfluramine (NF). In order to assess the role of 5HT2B receptor activation, the effects of these drugs were also tested with a 5HT2B receptor antagonist. After two weeks, tissue samples were stained immunohistochemically to localize changes in multiple extracellular matrix (ECM) components and synthesis mediators.


RESULTS
Decorin and versican expression tended to increase with 5HT treatment compared to NF or baseline controls, regardless of the presence of the receptor antagonist. Samples treated with 5HT or with the receptor antagonist tended to express less collagen (types I and III) and biglycan than NF or the baseline controls. Heat shock protein 47, prolyl-4-hydroxylase, matrix metalloproteinase 9 (MMP9) and MMP13 tended to be down-regulated with 5HT or NF exposure, although some samples treated with the antagonist displayed normal levels of these mediators. Superficial plaques grew on a subgroup of the NF-treated organ cultures, but on none of the 5HT and control valves.


CONCLUSIONS
Although both serotonin agents lead to plaque formation in a clinical setting, the early effects of exposure to the different drugs were found to be quite different. Additionally, the different drug responses suggest that a mechanism other than 5HT2B receptor activation might contribute to plaque formation.
Department of Bioengineering, Rice University, Houston, TX 77251-1892, USA.
Janet E
JE
Barzilla
Frances E
FE
Acevedo
K Jane
KJ
Grande-Allen
D000818:Animals; D019149:Bioreactors; D058575:Decorin / Q000378:metabolism; D004195:Disease Models, Animal; D006349:Heart Valve Diseases / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008943:Mitral Valve / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D009642:Norfenfluramine / Q000494:pharmacology; D009924:Organ Culture Techniques; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D013552:Swine; D053675:Versicans / Q000378:metabolism
D058575:Decorin; D018490:Serotonin Agents; D053675:Versicans; D009642:Norfenfluramine; D012701:Serotonin; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9