AI Article Synopsis

  • Increased serotonin signaling is linked to structural changes in heart valves, particularly in the mitral valve, where reduced serotonin transporter (SERT) expression worsens degenerative mitral valve regurgitation.
  • Mice lacking SERT show significant heart issues, including fibrosis, reduced heart function, and abnormal heart sizes, with differences in gene expression patterns occurring at different ages between heart valves.
  • Valve interstitial cells from the mitral valve react more strongly to serotonin and TGFβ1 compared to other valves, suggesting that downregulation of SERT may make the heart more prone to pro-fibrotic changes, particularly in the mitral valve, which is also observed in human valve cells.

Article Abstract

Increased serotonin (5HT) concentration and signaling, can lead to pathological remodeling of the cardiac valves. We previously showed that a reduction of the 5HT transporter (SERT) expression in the mitral valve (MV) contributes to the progression of degenerative MV regurgitation (MR). We sought to investigate the myocardial and valvular phenotype of SERT mice in order to identify remodeling mechanisms specific to the MV and left ventricular (LV) remodeling. Using 8- and 16-week-old WT and SERT mice we show that male and female animals deficient of SERT have pathological remodeling of the cardiac valves, myocardial fibrosis, diminished ejection fraction and altered left ventricular dimensions. In the MV and intervalvular area of the aortic valve (AV)-MV, gene expression, including Col1a1 mRNA, was progressively altered with age up until 16 weeks of age. In contrast, in the AV and myocardium, most gene expression changes occurred earlier and plateaued by 8 weeks. To explore basal differences in susceptibility to remodeling stimuli among cardiac valves, valve interstitial cells (VIC) were isolated from AV, MV, tricuspid valve (TV), pulmonary valve (PV) and fibroblasts (Fb) from the myocardial apex from 16 weeks old wild type (WT) mice. After 24h stimulation with 10 µM of 5HT, the gene expression of Col1a1 and Acta2 were upregulated in MVIC to a higher degree than in VIC from other valves and Fb. Treatment with TGFβ1 similarly upregulated Cola1 and Acta2 in MVIC and AVIC, while the increase was milder in right heart VIC and Fb. Experiments were also carried out with human VIC. In comparison to mice, human left heart VIC were more sensitive to 5HT and TGFβ1, upregulating COL1A1 and ACTA2; TGFβ1 upregulated HTR2B expression in all VIC. Our results support the hypothesis that a deleterious cardiac effect of SERT downregulation may be mediated by increased susceptibility to HTR2B-dependent pro-fibrotic mechanisms, which are distinct among VIC populations and cardiac fibroblasts, regardless of SERT activity. Given that HTR2B mechanisms involved in VIC and myocardial remodeling response are due to both 5HT and also to downstream related TGFβ1 and TNFα activity, targeting HTR2B could be a therapeutic strategy for dual treatment of MR and LV remodeling.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11585425PMC
http://dx.doi.org/10.1016/j.carpath.2024.107689DOI Listing

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