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The Selective Serotonin 2A Receptor Antagonist Sarpogrelate Prevents Cardiac Hypertrophy and Systolic Dysfunction via Inhibition of the ERK1/2–GATA4 Signaling Pathway
| Content Provider | MDPI |
|---|---|
| Author | Shimizu, Kana Sunagawa, Yoichi Funamoto, Masafumi Honda, Hiroki Katanasaka, Yasufumi Murai, Noriyuki Kawase, Yuto Hirako, Yuta Katagiri, Takahiro Yabe, Harumi Shimizu, Satoshi Sari, Nurmila Wada, Hiromichi Hasegawa, Koji Morimoto, Tatsuya |
| Copyright Year | 2021 |
| Description | 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 $(5-HT_{2A}$) 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 $5-HT_{2A}$ 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. |
| Starting Page | 1268 |
| e-ISSN | 14248247 |
| DOI | 10.3390/ph14121268 |
| Journal | Pharmaceuticals |
| Issue Number | 12 |
| Volume Number | 14 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-12-05 |
| Access Restriction | Open |
| Subject Keyword | Pharmaceuticals Peripheral Vascular Disease Sarpogrelate 5-ht2a Receptor Drug Repositioning Erk1/2–gata4 Pathway Heart Failure |
| Content Type | Text |
| Resource Type | Article |
