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

2021 ◽  
Vol 14 (12) ◽  
pp. 1268
Author(s):  
Kana Shimizu ◽  
Yoichi Sunagawa ◽  
Masafumi Funamoto ◽  
Hiroki Honda ◽  
Yasufumi Katanasaka ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Receptor Antagonist ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Systolic Dysfunction ◽  
Selective Serotonin ◽  
Cardiomyocyte Hypertrophy ◽  
Serotonin 2A ◽  
Cultured Cardiomyocytes

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.

Abstract 16402: Epa and Dha Suppressed Myocardial Infarction-induced Systolic Dysfunction by Inhibiting P300 Hat Activity

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Masafumi Funamoto ◽  
Yoichi Sunagawa ◽  
Yasufumi Katanasaka ◽  
Kana Shimizu ◽  
Yusuke Miyazaki ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Systolic Dysfunction ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Omega 3 ◽  
Direct Inhibition ◽  
Epa And Dha ◽  
Cultured Cardiomyocytes

Introduction: p300, an intrinsic histone acetyltransferase (HAT), has a crucial role in the pathological cardiac hypertrophy and the development of heart failure in vivo . Although many studies have shown a cardioprotective effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 fatty acids, little is known about the effects of these acids on cardiac hypertrophy. Aim: This study investigated whether EPA and DHA inhibited the development of heart failure in rats with myocardial infarction (MI). Methods and Results: To investigate the effects on cardiomyocyte hypertrophy in cultured cardiomyocytes, neonatal rat cultured cardiomyocytes were stimulated with phenylephrine (PE). EPA or DHA significantly inhibited PE-induced cardiomyocyte hypertrophy. EPA and DHA repressed to the same extent PE-induced acetylation of histone H3 in cultured cardiomyocytes. An in vitro HAT assay was performed to determine the direct inhibition of p300-HAT activity. The results revealed that EPA and DHA significantly inhibited p300-HAT activity. To assess whether EPA and DHA suppress p300-HAT activity directly in cultured cardiomyocytes, p300 was overexpressed in cultured cardiomyocytes. Treatment with EPA or DHA inhibited the overexpression of p300-induced cardiomyocyte hypertrophy in cultured cardiomyocytes. MI-operated rats (FS < 40%) were randomly assigned to 3 groups: vehicle, EPA (1 g/kg) and DHA (1 g/kg). One week after MI operation, oral administrations were repeated for 6 weeks. Echocardiographic analysis demonstrated that EPA and DHA significantly improved MI-induced cardiac dysfunction. In addition, Masson's trichrome staining showed that EPA and DHA inhibit MI-induced fibrosis response in MI rats. EPA and DHA repressed MI-induced hypertrophic response gene transcriptions such as ANF and BNP with RT-PCR. Western blotting demonstrated that inhibited MI-induced H3K9 acetylation in rats . Conclusion: EPA and DHA suppressed hypertrophic responses to the same extent, through the direct inhibition of p300-HAT activity and repressed MI-induced development of heart failure.

Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice

Planta Medica ◽  
2020 ◽  
Vol 86 (17) ◽  
pp. 1304-1312
Author(s):  
Nurmila Sari ◽  
Yasufumi Katanasaka ◽  
Hiroki Honda ◽  
Yusuke Miyazaki ◽  
Yoichi Sunagawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Gene Transcription ◽  
Binding Protein ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

AbstractPathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.

Abstract 16343: Sarpogrelate, a Selective Serotonin 2a Receptor Antagonist, Suppresses Pressure Overlaod-induced Cardiac Hypertrophy and Systolic Dysfunction Through Inhibiting Erk1/2/gata4 Pathway

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kana Shimizu ◽  
Masafumi Funamoto ◽  
Yoichi Sunagawa ◽  
Yasufumi Katanasaka ◽  
Yusuke Miyazaki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Receptor Antagonist ◽  
Surface Area ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Cell Diameter ◽  
Sham Operation ◽  
Mrna Levels ◽  
Wide Range

Introduction: Serotonin (5-HT), a neurohormone involved in a wide range of physiological functions, has generated much interest in recent years regarding its potential role in cardiac function. It is reported that sarpogrelate, a selective 5-HT2A receptor antagonist, possesses cardioprotective effect against myocardial infarction, however, the precise molecular mechanism of the effect is still unclear. In this study, we examined the effect of sarpogrelate on pressure overload-induced development of heart failure, another heart failure model. Methods: First, primary cultured cardiomyocytes were treated with 1 μM sarpogrelate and then stimulated with various hypertrophic stimuli. Cardiomyocytes were stained with anti-actinin antibody and the surface area of the cells were measured. The phosphorylation levels of ERK1/2 and GATA4 were assessed by western blotting. 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. Results: Sarpogrelate significantly suppressed an increase in the surface area of cardiomyocytes induced not only by 5-HT, but also by phenylephrine, angiotensin II and ET-1. Sarpogrelate suppressed phenylephrine-induced phosphorylation of ERK1/2 and GATA4. In a mice model of heart failure, 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. One mg/kg sarpogrelate also suppressed TAC-induced increase in HW/BW ratio, myocardial cell diameter and the mRNA levels of ANF and BNP. Moreover, 1 mg/kg sarpogrelate significantly suppressed TAC-induced phosphorylation of ERK1/2. Conclusions: These results indicate that 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.

P1618A polymethoxy flavonoid, Nobiletin, Has a therapeutic potency against the development of heart failure through NBP1 activation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Sunagawa ◽  
M Funamoto ◽  
K Shimizu ◽  
S Shimizu ◽  
Y Katanasaka ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Natural Compound ◽  
Binding Protein ◽  
Systolic Dysfunction ◽  
Myocardial Cell ◽  
Cardiomyocyte Hypertrophy ◽  
Target Molecule ◽  
Cell Hypertrophy

Abstract Introduction Maladaptive hypertrophy is being recognized as a critical event during the development of heart failure. The control of cardiac hypertrophy may be one of the therapeutic strategy for heart failure therapy. In our previous study, we screened natural compound library and found that a natural compound, Nobiletin, could inhibit cardiomyocyte hypertrophy in culture. Nobiletin has various useful effects such as anti-cancer, anti-inflammation, and anti-oxidant and may be applicable to pharmacological therapy for heart failure. Hypothesis We thought that nobiletin might prevent the development of heart failure in vivo and investigated the target molecule of Nobiletin in the heart. Methods and results In primary cardiomyocytes, Nobiletin significantly inhibited phenylephrine (PE)-induced hypertrophic responses such as increases in cell size and hypertrophic gene transcription, such as ANF and BNP. C57BL6 mice were subjected to sham or transarotic constriction (TAC). Oral administrations of Nobiletin (20 mg/kg/day) or vehicle were repeated for 8 weeks. Nobiletin treatment significantly prevented TAC-induced increases in PWT and systolic dysfunction. Nobiletin also suppressed TAC-induced myocardial cell hypertrophy, perivascular fibrosis, and hypertrophic gene transcriptions. To investigate the target molecule of Nobiletin, Nobiletin-binding proteins were purified from rat heart using biotin-conjugated Nobiletin. We identified 162 novel binding protein of Nobiletin by LC/MS-MS. One of them, Nobiletin-binding protein 1 (NBP1) related to cellular metabolic pathway. Pulldown assay demonstrated that biotin-conjugated Nobiletin, but not biotin, directly interacted with recombinant NBP1. In vitro enzyme assay showed that Nobiletin enhanced NBP1 activity. Although NBP1 knockdown could not affect PE-induced hypertrophic response gene transcriptions and cardiomyocyte hypertrophy, NBP1 knockdown failed to exhibit Nobiletin-mediated anti-hypertrophic effects. NBP1-KO mice and WT mice were subjected to sham or TAC and randomly divided into two groups: Nobiletin (20 mg/kg/day) and vehicle. After 8 weeks, Nobiletin significantly improved TAC-induced cardiac hypertrophy and systolic dysfunction in WT mice but not in NBP1-KO mice. Nobiletin also prevented TAC-induced increases in HW/BW rate, myocardial cell hypertrophy, and mRNA levels of ANF and β-MHC in WT mice but not in NBP1-KO mice. Conclusions In this study, we demonstrate that Nobiletin inhibits cardiomyocyte hypertrophy and the development of heart failure in vivo. NBP1 activity is required to exhibit therapeutic potency of Nobiletin for heart failure. These finding suggest that a natural compound, nobiletin, might be a candidate for heart failure agent in human. Acknowledgement/Funding This work was supported by JSPS KAKENHI Grant.

scholarly journals Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Mayarling Francisca Troncoso ◽  
Mario Pavez ◽  
Carlos Wilson ◽  
Daniel Lagos ◽  
Javier Duran ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Cardiac Hypertrophy ◽  
Glucose Uptake ◽  
Male Rats ◽  
Cardiomyocyte Hypertrophy ◽  
Mrna Levels ◽  
Elevated Glucose ◽  
Amp Activated Protein Kinase ◽  
Cultured Cardiomyocytes

Abstract Background Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake—via AMP-activated protein kinase (AMPK)—after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). Methods Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of β-myosin heavy chain (β-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). Results Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated β-mhc, Hk2 and Pfk2 mRNA levels. Conclusion These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.

scholarly journals Betulinic Acid Protects DOX-Triggered Cardiomyocyte Hypertrophy Response through the GATA-4/Calcineurin/NFAT Pathway

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 53
Author(s):  
Jung Joo Yoon ◽  
Chan Ok Son ◽  
Hye Yoom Kim ◽  
Byung Hyuk Han ◽  
Yun Jung Lee ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Betulinic Acid ◽  
Cardiomyocyte Hypertrophy ◽  
Ros Generation ◽  
H9c2 Cells ◽  
Myosin Light Chain 2 ◽  
Cardiovascular Morbidity And Mortality

Cardiac hypertrophy is a major risk factor for heart failure and leads to cardiovascular morbidity and mortality. Doxorubicin (DOX) is regarded as one of the most potent anthracycline antibiotic agents; however, its clinical usage has some limitations because it has serious cardiotoxic side effects such as dilated cardiomyopathy and congestive heart failure. Betulinic acid (BA) is a pentacyclic-cyclic lupane-type triterpene that has been reported to have anti-bacterial, anti-inflammatory, anti-vascular neogenesis, and anti-fibrotic effects. However, there is no study about its direct effect on DOX induced cardiac hypertrophy and apoptosis. The present study aims to investigate the effect of BA on DOX-induced cardiomyocyte hypertrophy and apoptosis in vitro in H9c2 cells. The H9c2 cells were stimulated with DOX (1 µM) in the presence or absence of BA (0.1–1 μM) and incubated for 24 h. The results of the present study indicated that DOX induces the increase cell surface area and the upregulation of hypertrophy markers including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta-myosin heavy chain (β-MHC), and Myosin Light Chain-2 (MLC2) in H9c2 cells. However, the pathological hypertrophic responses were downregulated after BA treatment. Moreover, phosphorylation of JNK, ERK, and p38 in DOX treated H9c2 cells was blocked by BA. As a result of measuring the change in ROS generation using DCF-DA, BA significantly inhibited DOX-induced the production of intracellular reactive oxygen species (ROS) when BA was treated at a concentration of over 0.1 µM. DOX-induced activation of GATA-4 and calcineurin/NFAT-3 signaling pathway were remarkably improved by pre-treating of BA to H9c2 cells. In addition, BA treatment significantly reduced DOX-induced cell apoptosis and protein expression levels of Bax and cleaved caspase-3/-9, while the expression of Bcl-2 was increased by BA. Therefore, BA can be a potential treatment for cardiomyocyte hypertrophy and apoptosis that lead to sudden heart failure.

scholarly journals Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thanachai Methatham ◽  
Shota Tomida ◽  
Natsuka Kimura ◽  
Yasushi Imai ◽  
Kenichi Aizawa
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Left Ventricular ◽  
Cardiac Wall ◽  
Macrophage Marker ◽  
Glycolysis Pathway ◽  
Canonical Wnt ◽  
Macrophage Accumulation

AbstractIn heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes β-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, β-MHC, and β-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/β-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.

Abstract P352: An Antiplatelet Agent Sarpogrelate Suppresses Pressure Overload-induced Development Of Heart Failure In A 5-ht 2a Receptor-independent Manner

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Kana Shimizu ◽  
Masafumi Funamoto ◽  
Yoichi Sunagawa ◽  
Yasufumi Katanasaka ◽  
Yusuke Miyazaki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Western Blotting ◽  
Drug Repositioning ◽  
Antiplatelet Agent ◽  
Left Ventricular ◽  
Antiplatelet Drug ◽  
Cardiomyocyte Hypertrophy ◽  
Sham Operation ◽  
Mrna Levels ◽  
Independent Manner

Purpose: The cost of new drug development is increasing year by year, and drug repositioning is being used as a strategy to develop new treatments at low-cost. We used a library of approved drugs to screen for compounds that suppress cardiomyocyte hypertrophy, and identified as a candidate the antiplatelet drug sarpogrelate, a selective serotonin-2A (5-HT 2A ) receptor antagonist. In this study, we examined 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). The results of immunofluorescence staining with anti-MHC antibody showed that sarpogrelate significantly suppressed cardiomyocyte hypertrophy induced by each stimulus. Western blotting and qPCR analysis showed that the mRNA and protein levels of 5-HT 2A receptor did not change by PE, and sarpogrelate significantly suppressed PE-induced 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 TAC-induced increase in HW/BW ratio, cross-sectional areas, perivascular fibrosis, and mRNA levels of ANF and BNP. Moreover, the western blotting analysis showed that 5 mg/kg sarpogrelate significantly suppressed TAC-induced phosphorylation of ERK1/2. Conclusions: These results indicate that 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.

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