The Selective Serotonin 2A Receptor Antagonist Sarpogrelate Prevents Cardiac Hypertrophy and Systolic Dysfunction via Inhibition of the ERK1/2-GATA4 Signaling Pathway.

Kana Shimizu,Masafumi Funamoto,Noriyuki Murai,Yuta Hirako,Takahiro Katagiri,Satoshi Shimizu,Koji Hasegawa,Tatsuya Morimoto,Harumi Yabe,Nurmila Sari,Hiroki Honda,Yasufumi Katanasaka,Yoichi Sunagawa,Yuto Kawase,Hiromichi Wada

doi:10.3390/ph14121268

Kana Shimizu, Masafumi Funamoto + Show 13 more

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https://doi.org/10.3390/ph14121268

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Abstract

Drug repositioning has recently emerged as a strategy for developing new treatments at low cost. In this study, we used a library of approved drugs to screen for compounds that suppress cardiomyocyte hypertrophy. We identified the antiplatelet drug sarpogrelate, a selective serotonin-2A (5-HT2A) receptor antagonist, and investigated the drug’s anti-hypertrophic effect in cultured cardiomyocytes and its effect on heart failure in vivo. Primary cultured cardiomyocytes pretreated with sarpogrelate were stimulated with angiotensin II, endothelin-1, or phenylephrine. Immunofluorescence staining showed that sarpogrelate suppressed the cardiomyocyte hypertrophy induced by each of the stimuli. Western blotting analysis revealed that 5-HT2A receptor level was not changed by phenylephrine, and that sarpogrelate suppressed phenylephrine-induced phosphorylation of ERK1/2 and GATA4. C57BL/6J male mice were subjected to transverse aortic constriction (TAC) surgery followed by daily oral administration of sarpogrelate for 8 weeks. Echocardiography showed that 5 mg/kg of sarpogrelate suppressed TAC-induced cardiac hypertrophy and systolic dysfunction. Western blotting revealed that sarpogrelate suppressed TAC-induced phosphorylation of ERK1/2 and GATA4. These results indicate that sarpogrelate suppresses the development of heart failure and that it does so at least in part by inhibiting the ERK1/2–GATA4 signaling pathway.

Highlights

Heart failure is a serious public health problem, with an estimated 64 million cases under treatment globally each year [1,2]
To investigate the effect of sarpogrelate on cardiomyocyte hypertrophy induced by various types of hypertrophic stimuli, primary cultured cardiomyocytes were pretreated with 1 μM sarpogrelate, and cell hypertrophy was induced separately with the hypertrophic stimuli PE, angiotensin II (Ang II), and endothelin1 (ET-1) for 48 h
The results showed that sarpogrelate suppressed PE-induced atrial natriuretic factor (ANF)- (Figure 1c) and ET-1-luciferase (Figure 1d) expression

Summary

Introduction

Heart failure is a serious public health problem, with an estimated 64 million cases under treatment globally each year [1,2]. As the number of people suffering from the disease is expected to continue increasing over the coming decades, heart failure is one of the most significant health problems worldwide [3,4]. Neurohormonal antagonists, including β blockers, and renin-angiotensin system inhibitors are the established standards for heart failure therapy, based on clinical studies demonstrating that these drugs suppress cardiac remodeling and improve prognosis [5,6]. As prognosis remains poor even with the use of these drugs, new heart failure therapies are urgently needed [5,6].

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