Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice.

A Mekontso-Dessap, F Brouri, O Pascal, P Lechat, N Hanoun, L Lanfumey, I Seif, N Benhaiem-Sigaux, M Kirsch, M Hamon, S Adnot, S Eddahibi

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 651, Département de Physiologie, Université Paris XII, CHU Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France.

Circulation 2006 Jan 3

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Serotonin (5-hydroxytryptamine; 5-HT) overproduction is responsible for cardiac valvular disease in patients with carcinoid tumors. Reduced 5-HT inactivation is one proposed mechanism of the valvulopathy observed in individuals treated with the appetite suppressants fenfluramine and phentermine. One key protein limiting systemic availability of 5-HT is the 5-HT transporter (5-HTT) expressed by platelets and pulmonary vascular cells; 5-HTT is responsible for 5-HT uptake and subsequent inactivation of the amine passing through the lung. Here we investigated whether 5-HTT-deficient (5-HTT-KO) mice developed structural and/or functional cardiac abnormalities and valvulopathy. Cardiac endothelial cells expressed large amounts of 5-HTT in wild-type mice. 5-HTT deficiency appeared to be associated with marked interstitial, perivascular, and valvular fibrosis as evidenced by staining of cardiac collagen in 5-HTT-KO mice. Histological analysis provided evidence for valvulopathy characterized by valvular hyperplasia and prominent fibrosis at the attachment site and base of the leaflets. Echocardiography revealed an increase in left ventricular lumen diameter and a decrease in left ventricular diameter fractional shortening. Although 5-HT1B receptors mediated the 5-HT-induced collagen secretion by human cardiac myofibroblasts, the contribution of this receptor type to valvulopathy was ruled out because double-KO mice deficient in both 5-HTT and 5-HT1B receptors showed the same cardiac alterations as 5-HTT-KO mice. The present results establish a link between 5-HTT and the development of cardiac fibrosis and valvulopathy in vivo. 5-HTT-KO mice represent an especially relevant model for studying the mechanisms by which 5-HT induces valvulopathy.

Citation

A Mekontso-Dessap, F Brouri, O Pascal, P Lechat, N Hanoun, L Lanfumey, I Seif, N Benhaiem-Sigaux, M Kirsch, M Hamon, S Adnot, S Eddahibi. Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice. Circulation. 2006 Jan 3;113(1):81-9