# Serotonin transporter downregulation is associated with aortic stenosis, and early profibrotic remodeling is mitigated by pharmacological inhibition of HTR2B receptor

## TL;DR

This study shows that reduced serotonin transporter activity and increased HTR2B signaling contribute to aortic stenosis, and blocking HTR2B may help treat the condition.

## Contribution

The study identifies HTR2B as a novel therapeutic target for early fibro-calcific remodeling in aortic stenosis.

## Key findings

- AS patients show reduced SERT and increased HTR signaling, linked to fibro-calcific remodeling.
- Pharmacological inhibition of HTR2B reversed AngII-induced AV thickening and transcriptional changes in mice.
- Blocking HTR2B preserved AV structure and normalized pressure gradients in the mouse model.

## Abstract

Aortic Stenosis (AS) is a highly prevalent disease involving physiological and structural remodeling of aortic valve, yet lacks effective medical therapy to halt its progression. Serotonin (5HT) signaling has been implicated in valvular disease. We hypothesized that AS is associated with impaired 5HT clearance due to reduced serotonin receptor (SERT) expression and increased 5HT receptor (HTR) activity.

Sixty-six patients with severe AS undergoing aortic valve (AV) replacement were enrolled in the study, and samples from their explanted AV were harvested. Anatomically normal control AVs were obtained from transplant donors. Explanted AVs were collected for gene expression analysis and 5-HTTLPR genotyping. Gene expression was assessed by RT2-profiler gene array. In vivo, 8-week-old mice received 28-day Angiotensin-II (AngII) infusions ± HTR2B antagonist (LY272015) through subcutaneous Alzet osmotic-pump implants. AV structure and function were assessed via echocardiography, histology, and RNA sequencing. Human aortic valve interstitial cells (AVICs) were treated with AngII ± SERT siRNAs to assess 5HT signaling and profibrotic/procalcific markers.

AS patients exhibited reduced SERT and increased HTR signaling. AngII ± SERT siRNA promoted VIC osteogenic marker expression. In mice, AngII caused AV thickening, increased velocities and gradients, and activation of fibrosis and mildly calcification-related gene sets, including serotonin, TGFβ, Wnt/β-catenin, PI3K/Akt, and Notch pathways. Pharmacological inhibition of HTR2B preserved AV structure, normalized transvalvular velocities and pressure gradients, and reversed AngII-induced transcriptional changes.

In human and mouse AVs, reduced SERT expression and increased HTR2B signaling contribute to early-onset fibro-calcific remodeling. HTR2B inhibition by LY272015 reverses these effects, suggesting it as a potential therapeutic strategy for fibrotic remodeling in AS.