Hyperactivated Mek/erk Signaling As The Major Disease Initiating Pathway In Mitral Valve Prolapse
Tyler C. Beck1, Kendra Springs2, Jordan Morningstar1, Cortney Gensemer1, Leon Guo1, Rachel Biggs1, Kelsey Moore1, Menny Benjamin1, Natalie Koren1, Russell Norris1.
1Medical University of South Carolina, Charleston, SC, USA, 2College of Charleston, Charleston, SC, USA.
Objective: Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease, affecting 1 in 40 humans and ~70% of small breed dogs. There are no effective nonsurgical treatments for MVP and therapeutic efforts have been hindered due to an incomplete understanding of its fundamental causes. Our lab has identified the Mek/Erk pathway as the major disease initiating pathway and prolonged hyperactivation of Mek/Erk drives disease progression and severity. Thus, we hypothesize that aberraMek/Erk signaling is driving MVP pathogenesis and that pharmacological blockade will sufficiently arrest the disease pathway and maintain the valves in a sub-clinical condition. Methods/Results: Using immunohistochemistry (IHC) and Western blot analysis; we determined that Mek/Erk pathway activation was increased in human, canine, and mouse MVP patients relative to controls. To confirm that activation of this pathway is causative, we demonstrated that pERK1/2 is elevated prior to myxomatous degeneration (P0) and correlated with an activated cell type defined by α-SMA expression. Next, we tested a constitutively active Mek1 (caMek1) transgene (CAG-lox-STOP-lox-Mek1S217/221E+/-) that was bred to a periostinCre. By two-months of age, caMek1 mitral leaflets were dysmorphic and myxomatous appearing. These data indicate that hyperactivation of this pathway is sufficient to engender a valve phenotype reminiscent of myxomatous valve diseases. Using cobimetinib as bait, we performed an analog search in ChemSpace and identified a novel scaffold selective for MEK1. We then modeled custom side-chains to optimize the binding characteristics and pharmacokinetic properties of our scaffold, resulting in superior MEK1 inhibitors to be used to treat MVP. Conclusions: Hyperactivated Mek/Erk signaling is a disease initiating pathway in the setting of MVP. Future studies will include screening our MEK1 inhibitors in vitro and in vivo. Results from this study may serve as a stepping-stone towards developing the first non-surgical treatment for patients with MVP.
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