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

Background: 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. Methods: 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. Results: 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, TGF Conclusions: 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.