Low Dose Galunisertib Halts Aortic Stenosis Progression By Inhibiting TGF-β Signaling In Mice
Kumar Subramani, Sandeep Subrahmanian, Rohan Varshney, Thamizhiniyan Venkatesan, Brienne Cortez, Pratibha Dube, Jasimuddin Ahamed.
Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Objective: Aortic stenosis (AS) is a degenerative valve disease characterized by increased fibrosis and calcification in the aortic valve (AV). Persistent severe AS leads to heart failure and sudden death. There is no treatment for AS other than valve replacement. Elevated plasma levels of TGF-β1 are observed in AS patients. Platelet-derived TGF-β1 is a major source of plasma TGF-β1, which contributes to AS progression in LDLR-/-ApoB100/100 (LDLR), a mouse model of AS. We hypothesize that galunisertib (an oral small-molecule inhibitor of TGF-β signaling, currently in several clinical trials for cancer) will inhibit AS progression. Methods: We treated 6-month-old LDLR mice with moderate AS with galunisertib (1uM in drinking water) and measured AS progression at 12 months of age (when they developed severe AS) by our modified ultrasound imaging. TGF-β signaling in aortic valve cells were measured by immunohistochemistry. Results: Galunisertib inhibited TGF-β1-induced in PAI-1 promoter activity in a dose-dependent manner, with an IC50 ≤ 0.1 uM, a concentration, 100-fold less than used in clinical trials. Low-dose of galunisertib (1uM) treatment halted AS progression in LDLR mice compared to vehicle-treated control LDLR mice (fractional aortic valve cusp separation was 0.5 in control and 0.7 in galunisertib, p=0.008, n=10). Galunisertib treatment resulted in ͠ 2-fold lower TGF-β signaling of p-Smad2, CD45+ cell numbers and periostin- and collagen- positive myofibroblasts in the AV compared to controls. Galunisertib treatment did not change blood cholesterol levels or heart functions in LDLR mice compared to vehicle-treated animals. Conclusions: Low-dose galunisertib treatment inhibits AS progression in the LDLR mouse model of AS, potentially by initiating platelet-derived TGF-β1-mediated signaling. Future pharmacokinetic/pharmacodynamic data are needed to motivate a clinical trial of galunisertib as a potential therapy for AS.
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