Abstract 10912: Sarpogrelate, an Antiplatelet Agent, Suppressed Cardiac Hypertrophy and Systolic Dysfunction in a 5-ht 2a Receptor-Independent Manner

Abstract

Introduction: Recently, the cost of new drug development is increasing year by year, and drug repositioning is being used as a strategy for developing new treatments by saving time and costs. We used a library of approved drugs to screen for compounds that suppress cardiomyocyte hypertrophy and identified the antiplatelet drug sarpogrelate, a selective serotonin-2A receptor antagonist, as a candidate for heart failure therapy. In this study, we investigated the effect of sarpogrelate on cultured cardiomyocyte hypertrophy and development of heart failure. Methods & Results: First, primary cultured cardiomyocytes were treated with 1 μM sarpogrelate and then stimulated with various hypertrophic stimuli (30 μM phenylephrine (PE), 0.1 μM angiotensin II and 0.1 μM endothelin 1). Sarpogrelate repressed hypertrophic responses induced by each stimulus, such as myofibrillar organization and increase in cell size. Moreover, PE-induced transactivation of the hypertrophic response genes promoter was significantly inhibited by sarpogrelate. Western blotting (WB) showed that sarpogrelate significantly suppressed PE-induced the phosphorylation of ERK1/2 and GATA4. Next, C57BL/6j male mice were subjected to a transverse aortic constriction (TAC) and sham operation. One day after the operation, the mice were randomly divided into 3 groups: sarpogrelate at 1 mg/kg or 5 mg/kg, and vehicle as a control. Daily oral administration was repeated for 8 weeks. Echocardiographic analysis showed that 5 mg/kg sarpogrelate significantly prevented a TAC-induced increase in posterior left ventricular wall thickness and a decrease in fractional shortening at 8 weeks after the operation. Five mg/kg sarpogrelate also suppressed a TAC-induced increase in HW/BW ratio, myocardial cell diameter, perivascular fibrosis, and mRNA levels of ANF and BNP. Moreover, the WB analysis showed that 5 mg/kg sarpogrelate significantly suppressed TAC-induced phosphorylation of the ERK1/2 and GATA4. Conclusions: Sarpogrelate significantly suppresses cardiomyocyte hypertrophy and the development of heart failure via at least, in part, by inhibition of ERK1/2-GATA4 pathway. These findings suggest that sarpogrelate may be an effective agent for heart failure therapy.