Effects of Serotonin and Cyclic Stretch on Aortic Valves
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Aortic valve (AV) disease is highly prevalent and a major source of mortality and morbidity. AV disease involves extensive extracellular remodeling of the aortic valve. Studies show that chronic use of anti-depressants, and adverse mechanical stimuli are individually correlated to AV degeneration through remodeling. There appears to be a synergistic mechanism between cyclic stretch of the AV and the disruption of 5-HT reuptake mechanism, a signaling pathway involved in various cellular functions. The objective of our study is to use an ex vivo system to understand the role of the combination of stretch and 5-HT reuptake mechanism in remodeling in AV disease. Fresh porcine AV were exposed to uniaxial cyclic stretch using a stretch bioreactor at 10% and 15% stretch for three days and concurrently treated with: normal media, 5-HT only, 5-HT with four sub-receptor inhibitors or 5-HT with a 5-HT transporter antagonist. A sircol collagen quantitative assay was used to quantify changes in the collagen content, as collagen is one of the hallmarks of valvular disease and remodeling. Additionally, immunohistochemistry was used for semi-quantitative analysis using collagen degradative marker and synthetic marker for analysis. While the addition of 5-HT significantly up regulated Heat Shock Protein-47, a common collagen molecular chaperone, 5-HT1D and 5-HT1A receptor inhibitors were most effective in down regulating HSP-47. Collagen levels of the 5-HT transporter correlated with the levels of matrix metalloprotease-1 degradation marker. Investigation of the sub-receptor and transporter parts of the 5-HT pathway illustrate that both the degradative and synthetic pathways are involved in the increase of collagen due to 5-HT. The results provide clues for design of novel pharmacological treatments to counter 5-HT induced valve degeneration, through blocking specific 5-HT receptors.