Serotonin Signaling in Mitral Valve Homeostasis, Maintenance and Restoration

SUMMARY Mitral regurgitation (MR) is a highly prevalent heart valve disease that affects millions, and for which there is no effective medication to prevent or mitigate progression. As a result, severe MR can only be treated with valve repair or replacement. Clinical and biological evidence, from us and other groups, has demonstrated a direct role of serotonin (5-HT) receptor (HTR) signaling in heart valve disease. The 5-HT transporter (SERT) deactivates 5-HT, thereby limiting HTR signaling. Prior studies by our group over the past 22 years led to our recent discovery that SERT expression and activity are reduced in MR leaflets compared to normal human mitral valve (MV) leaflets (nMV). These investigations have shown: 1) SERT downregulation in human mitral valve interstitial cells (MVIC) due to the activation of the mechano-sensing Ca++ channel, PIEZO1; 2) MVIC exposed to mechano- transduction events in vitro, simulating MR, demonstrate dysregulation of both PIEZO1 and SERT; and 3) Clinical use of antidepressants, that are SERT inhibitors, by MR patients has a significant hazard ratio for surgery at a younger age; 4) Pharmacologic inhibition of SERT, using Fluoxetine administration to mice, results in a mitral valvulopathy, that can be mitigated with a 5-HT-2B receptor (HTR2B) inhibitor. Our recent results with human MVIC, have shown that PIEZO1 activation leads to a 5-HT-dependent increase in collagen production, together with both down regulation of SERT, and reduced SERT activity; inhibition of either HTR2B or tryptophan hydroxylase-1, the enzyme responsible for 5-HT biosynthesis, mitigates MVIC increased collagen production, resulting from PIEZO1 activation. This novel set of experimental results, in our opinion, represents a major discovery concerning the connection between PIEZO1-activation and MR, as well fibrotic diseases with 5-HT dependence. In this proposal, we test the hypothesis that reduced SERT expression and activity in MR contributes to progression due to enhanced HTR signaling, that results from either: PIEZO1 activation leading to SERT down regulation in MVIC; mechanotransduction events that dysregulate both PIEZO1 and SERT, or pharmacological inhibition of SERT. To test this hypothesis we developed three independent, but connected aims. We will first dissect, at the cellular level, the pathway between PIEZO1 activation, reduced SERT activity, and downstream effects on HTR2B signaling. We will study the biomechanical mechanisms responsible for SERT down regulation in MR; and we will investigate the impact of pharmacologic inhibition or absence of SERT on MV pathophysiology.