Involvement of serotonin and 5-HT2 receptors in cardiac valve degeneration – SEROVALVE

Valvular heart disease encompasses a number of common cardiovascular conditions that account for 10% to 20% of all cardiac surgical procedures in developed countries. Although not as common as coronary cardiac disease, heart failure or hypertension, valvular heart disease is an important and challenging clinical entity. At the present time, no prospective pharmacological clinical trial has demonstrated any capability to affect the natural course of spontaneous native valve degeneration and/or the structural cardiac bioprostheses damage.
Recent safety data emphasized that a chronic exposure to therapeutically used compounds can induce cardiac valves degeneration. In fact, numerous drugs (methysergide, benfluorex, fenfluramine, MDMA, pergolide …) or their metabolites (methylergonovine, norfenfluramine, MDA) that activate a serotonergic receptor, 5-HT2B receptor, have been associated with degenerative valve disease. Carcinoid gut tumors, that release high amounts of 5-HT, are associated with the “carcinoid heart”, a cardiac valve disease presenting valve lesions similar to those induced by pharmacological compounds. However, direct experimental evidence for this receptor activation and function in heart valve disease is still missing as the possibility for therapeutic interventions by blocking this same receptor.
Given its negative history about valvular heart disease, the idea of targeting 5-HT2B receptors for therapeutic gain may initially seem counter-intuitive; however, studies have begun to explore the potential benefits of controlling 5-HT2B receptor signaling. Our own initial observations indicate that compounds blocking 5-HT2B receptors reduce fibrotic events in cardiopulmonary system. In our previous ANR SEROCARD, we have shown that serotonin via 5-HT2B receptors acts at cardiac ventricular fibroblasts as a necessary partner for angiotensin II and adrenergic stimulation to induced matrix metalloproteinases activation, cytokines release (IL-6, TNF-a, IL-1ß and TGF-ß) and fibrosis. In the same cells, a 5-HT2A stimulation can trigger proliferation, and migration of myofibroblasts. Independently, we have shown that 5-HT2B receptors are required for numerous fibrotic events including skin, liver and lung and for stem cells dependent processes. Therefore, serotonin contributes to drug-induced, carcinoid heart and spontaneous myxomatous cardiac valve degeneration by non yet determined serotonin effector pathways, the 5-HT2B receptor being a likely candidate.
The goal of the present proposal is to investigate cardiac valve and bioprostheses degeneration using a new approach by means of genetic, pharmacologic and molecular investigations in transgenic rodent models. In the present proposal, we intend to demonstrate experimentally that 5-HT2B receptors are crucial pathophysiological actors of cardiac valve degeneration. We will test this hypothesis in vitro (molecular and cellular biology) and in vivo in mice (serotonergic transgenic models, carcinoid heart mouse model, and stem cell migration). As a drugable target, we intend to demonstrate the interest of classical pharmacological antagonists against 5-HT2B receptors in cardiac serotonergic valve degeneration models.
The ultimate goal of this study will then to develop single domain antibodies (nanobodies) to be validated at first in blocking 5-HT2B receptor activation in vitro, and in vivo in fibrotic events in heart including primary indication of valvular heart disease. Our final objective is to propose such strategy for clinical applications in serotonergic cardiac valve degenerations and then to extend the applications towards other non-controlled fibrotic processes.