Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics of Notch1 heterozygous mice in a high-cholesterol diet model

Abstract

Calcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT2B serotonin receptor (gene: Htr2b) could improve the hemodynamic and histological progression of calcific aortic valve disease. Htr2b mutant mice were crossed with Notch1+/- mice, an established small animal model of CAVD, to determine if genetic ablation affects CAVD progression. To assess the effect of pharmacological inhibition on CAVD progression, Notch1+/- mice were treated with the 5-HT2B receptor antagonist SB204741. Mice were analyzed using echocardiography, histology, immunofluorescence, and real-time quantitative polymerase chain reaction. Htr2b mutant mice showed lower aortic valve peak velocity and mean pressure gradient–classical hemodynamic indicators of aortic valve stenosis–without concurrent left ventricle change. 5-HT2B receptor antagonism, however, did not affect hemodynamic progression. Leaflet thickness, collagen density, and CAVD-associated transcriptional markers were not significantly different in any group. This study reveals that genetic ablation of Htr2b attenuates hemodynamic development of CAVD in the Notch1+/- mice, but pharmacological antagonism may require high doses or long-term treatment to slow progression.

Serotonin—A Driver of Progressive Heart Valve Disease

“…In recent years genetic abnormalities, particularly in reduced Notch1 expression, have been regarded as a possible mechanism for calcification in CAVD (45). Interestingly, genetic ablation of the 5HT receptor 2B improved aortic valve hemodynamics of Notch1 heterozygous mice fed high-cholesterol diet (46). Actually, no effective pharmacologic treatment of CAVD has been found (42,47).…”

Targeting 5-HT 2B Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling After Myocardial Infarction

“…Quantitative image analysis was performed to extract area fractions using a previously described, custom MATLAB script. 61,69 Flow Isolation of CD31+ and CD45+ cells for qPCR and CFs for RNA sequencing was performed via FACS. Hearts were excised, and the atria and greater vessels were removed.…”

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

“…The 5-HT 2B R was shown to be involved in vascular heart diseases, including mitral valve prolapse (MVP) [21] and calcific aortic valve disease (CAVD) [22,23]. Overexpression of the 5-HT 2B R in the mitral valve leaflets was found in humans with MVP.…”

“…A study in isolated aortic valve interstitial cells (AVICs) in vitro showed that 5-HT 2B R antagonism could prevent AVIC activation, a process associated with CAVD [22]. Recently, the same research group reported that in a high cholesterol diet mouse model, aortic valve hemodynamic development of CAVD could be attenuated by the ablation of the 5-HT 2B gene, but not 5-HT 2B R antagonism [23].…”