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Mitogenic and secretory responses of human valve interstitial cells to vasoactive agents
S Hafizi1, P M Taylor, A H Chester
1Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Harefield Hospital, Middlesex, UK.
Background And Aim Of The Study:
The vasoactive agent 5-hydroxytryptamine (5-HT) has been implicated in valve disease due to possible trophic effects on valve interstitial cells (IC). The present study was aimed at characterizing the responses of cultured human heart valve IC to 5-HT in terms of intracellular calcium concentration ([Ca2+]i), mitogenesis and collagen synthesis. The effects of angiotensin II (Ang II) were also studied in parallel.
Methods:
IC were obtained by collagenase digestion of valve leaflets isolated from transplant recipient hearts. Changes in [Ca2+]i were measured from fluorescence of the ratiometric calcium dye, fura 2. Mitogenic and collagen synthetic responses of valve IC were measured by 3H-thymidine incorporation (DNA synthesis) and 3H-proline incorporation assays respectively, in quiescent cells.
Results:
Human valve IC responded to 5-HT and Ang II with mean maximal increases in [Ca2+]i of 249 +/- 47 nM and 397 +/- 159 nM, respectively. 5-HT stimulated DNA synthesis in quiescent IC, although to varying degrees among different isolations, with a maximum 43.4 +/- 20.1% increase by 10(-7) M 5-HT (p <0.05). Ang II did not stimulate IC DNA synthesis. Valve IC also responded to 5-HT with a maximum increase in collagen synthesis of 15.7 +/- 2.0% by 10(-6) M 5-HT (p <0.05). Ang II provoked a more powerful collagen synthesis response (maximum 50.5 +/- 15.1% increase by 10(-5) M Ang II; p <0.05).
Conclusion:
We have shown that 5-HT and Ang II promote the prolonged processes of growth and collagen synthesis in cultured human valve IC. Thus, these vasoactive agents may play a role in the development of heart valve disease.