Serotonin receptors and heart valve disease—It was meant 2B

Abstract

Carcinoid heart disease was one of the first valvular pathologies studied in molecular detail, and early research identified serotonin produced by oncogenic enterochromaffin cells as the likely culprit in causing changes in heart valve tissue. Researchers and physicians in the mid-1960s noted a connection between the use of several ergot-derived medications with structures similar to serotonin and the development of heart valve pathologies similar to those observed in carcinoid patients. The exact serotonergic target that mediated valvular pathogenesis remained a mystery for many years until similar cases were reported in patients using the popular diet drug Fen-Phen in the late 1990s. The Fen-Phen episode sparked renewed interest in serotonin-mediated valve disease, and studies led to the identification of the 5-HT2B receptor as the likely molecular target leading to heart valve tissue fibrosis. Subsequent studies have identified numerous other activators of the 5-HT2B receptor, and consequently, the use of many of these molecules has been linked to heart valve disease. Herein, we: review the molecular properties of the 5-HT2B receptor including factors that differentiate the 5-HT2B receptor from other 5-HT receptor subtypes, discuss the studies that led to the identification of the 5-HT2B receptor as the mediator of heart valve disease, present current efforts to identify potential valvulopathogens by screening for 5-HT2B receptor activity, and speculate on potential therapeutic benefits of 5-HT2B receptor targeting.

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…Chronic use of 5-HT 2B R agonists has been associated with cardiac valvulopathies and pulmonary hypertension [33], and a therapeutic strategy targeting 5-HT 2B R should consider the balance between potential benefits and cardiovascular risks in a currently intractable and rapidly progressive disease like ALS, in which patients are most often in good cardiovascular health. Since we identify common HTR2B polymorphisms as differentially associated with HTR2B expression in the CNS, eventual clinical studies should also take into account HTR2B genetic variations.…”

Kinetics of 5-HT2BReceptor Signaling: Profound Agonist-Dependent Effects on Signaling Onset and Duration

“…Activation of the receptor on heart valve interstitial cells is believed to result in abnormal deposition of extracellular matrix components, resulting in thickening of valve leaflets, ultimately producing valvular insufficiency or valvulopathy (Fitzgerald et al, 2000;Rothman et al, 2000;Huang et al, 2009;Rothman and Baumann, 2009;Elangbam, 2010;Hutcheson et al, 2011). The appetite suppressant fenfluramine, perhaps the most notorious valvulopathogen, was withdrawn from the US market in 1997.…”

Inhibition of 5‐Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β‐Arrestin2–Mammalian Target of Rapamycin/p70S6K Pathway

“…Compared with other 5‐HT receptor subtypes, 5‐HT2BR displays a lower expression in the brain, but is more abundantly expressed in the cardiovascular system, gastrointestinal tract, bone, and liver,25 suggesting that 5‐HT2BR may play a greater role in peripheral tissues. Previous studies have revealed important roles of 5‐HT2BR in the pathogeneses of vascular dysfunction and cardiac and valvular diseases 22, 23, 24, 25, 26, 27, 42.…”

“…5‐HT receptor 2B (5‐HT2BR) has a key role in the previously mentioned 5‐HT–related diseases, including cardiac hypertrophy, valve hyperplasia, and fibrosis 19, 20, 21. 5‐HT2BR induced hypersensitivity of arteries to 5‐HT in hypertension and PAH22, 23, 24, 25, 26, 27 and was required for vascular remodeling in PAH 22…”