Kathryn H Driesbaugh1, Emanuela Branchetti1, Juan B Grau2, Samuel J Keeney3, Kimberly Glass4, Mark A Oyama1, Nancy Rioux5, Salma Ayoub6, Michael S Sacks6, John Quackenbush4, Robert J Levy7, Giovanni Ferrari8. 1. University of Pennsylvania, Philadelphia, PA, United States. 2. University of Ottawa Heart Institute, Ottawa, Ontario, Canada. 3. University of Pennsylvania, Philadelphia, PA, United States; Columbia University, New York, NY, United States. 4. Dana Farber Cancer Center, Harvard University, Boston, MT, United States. 5. The Valley Hospital, Ridgewood, NJ, United States. 6. University of Texas at Austin, Austin, TX, United States. 7. The Children's Hospital of Philadelphia, Philadelphia, PA, United States. 8. Columbia University, New York, NY, United States. Electronic address: gf2375@cumc.columbia.edu.
Abstract
AIMS: Mitral valve interstitial cells (MVIC) play an important role in the pathogenesis of degenerative mitral regurgitation (MR) due to mitral valve prolapse (MVP). Numerous clinical studies have observed serotonin (5HT) dysregulation in cardiac valvulopathies; however, the impact of 5HT-mediated signaling on MVIC activation and leaflet remodeling in MVP have been investigated to a limited extent. Here we test the hypothesis that 5HT receptors (5HTRs) signaling contributes to MVP pathophysiology. METHODS AND RESULTS: Diseased human MV leaflets were obtained during cardiac surgery for MVP; normal MV leaflets were obtained from heart transplants. MV RNA was used for microarray analysis of MVP patients versus control, highlighting genes that indicate the involvement of 5HTR pathways and extracellular matrix remodeling in MVP. Human MV leaflets were also studied in vitro and ex vivo with biomechanical testing to assess remodeling in the presence of a 5HTR2B antagonist (LY272015). MVP leaflets from Cavalier King Charles Spaniels were used as a naturally acquired in vivo model of MVP. These canine MVP leaflets (N=5/group) showed 5HTR2B upregulation. This study also utilized CB57.1ML/6 mice in order to determine the effect of Angiotensin II infusion on MV remodeling. Histological analysis showed that MV thickening due to chronic Angiotensin II remodeling is mitigated by a 5HTR2B antagonist (LY272015) but not by 5HTR2A inhibitors. CONCLUSION: In humans, MVP is associated with an upregulation in 5HTR2B expression and increased 5HT receptor signaling in the leaflets. Antagonism of 5HTR2B mitigates MVIC activation in vitro and MV remodeling in vivo. These observations support the view that 5HTR signaling is involved not only in previously reported 5HT-related valvulopathies, but it is also involved in the pathological remodeling of MVP.
AIMS: Mitral valve interstitial cells (MVIC) play an important role in the pathogenesis of degenerative mitral regurgitation (MR) due to mitral valve prolapse (MVP). Numerous clinical studies have observed serotonin (5HT) dysregulation in cardiac valvulopathies; however, the impact of 5HT-mediated signaling on MVIC activation and leaflet remodeling in MVP have been investigated to a limited extent. Here we test the hypothesis that 5HT receptors (5HTRs) signaling contributes to MVP pathophysiology. METHODS AND RESULTS: Diseased human MV leaflets were obtained during cardiac surgery for MVP; normal MV leaflets were obtained from heart transplants. MV RNA was used for microarray analysis of MVP patients versus control, highlighting genes that indicate the involvement of 5HTR pathways and extracellular matrix remodeling in MVP. Human MV leaflets were also studied in vitro and ex vivo with biomechanical testing to assess remodeling in the presence of a 5HTR2B antagonist (LY272015). MVP leaflets from Cavalier King Charles Spaniels were used as a naturally acquired in vivo model of MVP. These canine MVP leaflets (N=5/group) showed 5HTR2B upregulation. This study also utilized CB57.1ML/6 mice in order to determine the effect of Angiotensin II infusion on MV remodeling. Histological analysis showed that MV thickening due to chronic Angiotensin II remodeling is mitigated by a 5HTR2B antagonist (LY272015) but not by 5HTR2A inhibitors. CONCLUSION: In humans, MVP is associated with an upregulation in 5HTR2B expression and increased 5HT receptor signaling in the leaflets. Antagonism of 5HTR2B mitigates MVIC activation in vitro and MV remodeling in vivo. These observations support the view that 5HTR signaling is involved not only in previously reported 5HT-related valvulopathies, but it is also involved in the pathological remodeling of MVP.
Authors: Nassir M Thalji; Michael A Hagler; Heyu Zhang; Grace Casaclang-Verzosa; Asha A Nair; Rakesh M Suri; Jordan D Miller Journal: Circ Cardiovasc Genet Date: 2015-03-26
Authors: Rachana Sainger; Juan B Grau; Emanuela Branchetti; Paolo Poggio; William F Seefried; Benjamin C Field; Michael A Acker; Robert C Gorman; Joseph H Gorman; Clark W Hargrove; Joseph E Bavaria; Giovanni Ferrari Journal: J Cell Physiol Date: 2012-06 Impact factor: 6.384
Authors: Emanuela Branchetti; Rachana Sainger; Paolo Poggio; Juan B Grau; Jeffrey Patterson-Fortin; Joseph E Bavaria; Michael Chorny; Eric Lai; Robert C Gorman; Robert J Levy; Giovanni Ferrari Journal: Arterioscler Thromb Vasc Biol Date: 2012-12-13 Impact factor: 8.311
Authors: Mark A Oyama; Chad Elliott; Kerry A Loughran; Alexander P Kossar; Estibaliz Castillero; Robert J Levy; Giovanni Ferrari Journal: Cardiovasc Pathol Date: 2020-01-07 Impact factor: 2.185
Authors: Jacqueline H Fortier; Beatrice Pizzarotti; Richard E Shaw; Robert J Levy; Giovanni Ferrari; Juan Grau Journal: Heart Date: 2019-05-25 Impact factor: 5.994
Authors: J Caleb Snider; Lance A Riley; Noah T Mallory; Matthew R Bersi; Prachi Umbarkar; Rekha Gautam; Qinkun Zhang; Anita Mahadevan-Jansen; Antonis K Hatzopoulos; Luc Maroteaux; Hind Lal; W David Merryman Journal: Circulation Date: 2021-01-21 Impact factor: 29.690