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-HT(2B) receptor as the likely molecular target leading to heart valve tissue fibrosis. Subsequent studies have identified numerous other activators of the 5-HT(2B) 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-HT(2B) receptor including factors that differentiate the 5-HT(2B) receptor from other 5-HT receptor subtypes, discuss the studies that led to the identification of the 5-HT(2B) receptor as the mediator of heart valve disease, present current efforts to identify potential valvulopathogens by screening for 5-HT(2B) receptor activity, and speculate on potential therapeutic benefits of 5-HT(2B) receptor targeting.

Fig. 1

Molecular structure of serotonin.

Fig. 2

A three-dimensional homology model of the 5-HT2B receptor. The model is based on the crystal structure of squid rhodopsin, which has a high degree of homology with the 5-HT2B receptor. Shown are two TM3 residues and one TM6 residue known to interact with serotonin.

Fig. 3

Schematic of blood flow through the four heart chambers. Blood from the body returns to the right atrium of the heart through the vena cava and proceeds to the right ventricle through the tricuspid valve. The ventricle pumps this deoxygenated blood through the pulmonary valve to the lungs. Oxygenated blood from the lungs returns to the left atrium through the pulmonary veins. The blood then proceeds through the mitral valve to the left ventricle; whereupon, it is pumped through the aortic valve for systemic distribution. Reprinted with permissions from the National Heart, Lung, and Blood Institute, a part of the National Institutes of Health and the U.S. Department of Health and Human Services.

Fig. 4

Structures of heart valves. (a) The three-leaflet aortic valve is shown in both its open (systolic) and closed (diastolic) states. The pulmonary valve is very similar in structure to the aortic valve. Reprinted with permissions from (Schoen and Edwards 2001). (b) The two leaflet mitral valve is anchored to the ventricular wall by chordae tendineae and papillary muscles to prevent prolapsed into the atrium during systole. The tricuspid valve is anchored in a similar manner as the mitral valve but contains three leaflets. Reprinted with permissions from (Grashow, Yoganathan et al. 2006).

Fig. 5

5-HT₂ receptor subtype expression in the aortic valve. 5-HT_2A and 5-HT_2B receptors are expressed in much greater numbers than 5-HT_2C as shown by random primed cDNA (solid bars) or oligo(dT) data (hatched bars). Reprinted with permissions from (Fitzgerald, Burn et al. 2000).

Fig. 6

Potential pathways of 5-HT_2B. 5-HT_2B activation may lead to proliferation through pathways that depend on ERK1/2, Src, and PKC. Additionally, 5-HT_2B may crosstalk directly with TGF-β1 signaling via interaction with Src. A 5-HT_2B antagonist may function as an inverse agonist to inhibit these pathways and prevent the fibrotic response of VICs that leads to HVD. Reprinted with permissions from (Roth 2007).