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.

Abstract 17094: The Curcumin Analogue GO-Y030 Effectively Suppresses Cardiac Hypertrophy and Systolic Dysfunction Through p300-HAT Inhibition

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Kana Shimizu ◽  
Masafumi Funamoto ◽  
Yoichi Sunagawa ◽  
Yasufumi Katanasaka ◽  
Yusuke Miyazaki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Therapeutic Potential ◽  
Systolic Dysfunction ◽  
Cardiomyocyte Hypertrophy ◽  
Cell Diameter ◽  
Sham Operation ◽  
Mrna Levels ◽  
Curcumin Analog ◽  
H3k9 Acetylation

Introduction: We previously found that a natural p300 histone acetyltransferase (HAT) inhibitor, curcumin, suppresses the development of heart failure. However, curcumin has low bioavailability; therefore, it is important to find analogues to it to enhance its therapeutic potential. In the present study, we focused on C 5 -curcuminoids, which possess stronger anti-cancer activity than curcumin, and investigated whether they inhibit p300-HAT activity, and therefore whether they may be useful as therapeutic agents for heart failure. Methods & Results: First, an in vitro p300 HAT assay revealed that the IC 50 value of GO-Y030, one of the C 5 -curcumin analogues investigated, was 1.1 μM, while that of curcumin was 9.4 μM. Moreover, the assay revealed that both mono-ketone moiety and 4 alkoxy groups (3, 3’, 5, 5’) were important for the enhancement of p300-HAT inhibition of GO-Y030. Second, cultured cardiomyocytes were treated with GO-Y030 or curcumin and then stimulated with phenylephrine (PE). 1 μM of GO-Y030 suppressed the following effects to the same extent as 10 μM of curcumin: PE-induced histone H3K9 acetylation, increases in the mRNA levels of ANF and BNP, and an increase in the surface area of cardiomyocytes. Third, C57BL/6j male mice were subjected to transverse aortic constriction (TAC) or sham operation. One day after the operation, TAC mice were randomly assigned to five groups: vehicle, 1 or 50 mg/kg curcumin, and 0.1 or 0.5 mg/kg GO-Y030. Oral administrations were repeated for 6 weeks. Echocardiographic analysis showed that 0.5 mg/kg GO-Y030 prevented a TAC-induced increase in posterior wall thickness and systolic dysfunction to the same extent as 50 mg/kg curcumin. Moreover, 0.5 mg/kg GO-Y030 suppressed increases in HW/BW ratio, myocardial cell diameter, perivascular fibrosis, mRNA levels of ANF and BNP, and histone H3K9 acetylation to the same extent as 50 mg/kg curcumin. Conclusions: These results indicate that the curcumin analog GO-Y030 strongly inhibits p300-HAT activity compared to curcumin and its derivatives in vitro , and that a low dose of GO-Y030 prevented both cardiomyocyte hypertrophy and the development of heart failure. These findings suggest that GO-Y030 may be more effective than curcumin for heart failure therapy.

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.

Abstract P381: Ecklonia Stolonifera Okamura Extract Suppresses Hypertrophic Responses In Cardiomyocytes And Development Of Heart Failure By Inhibiting P300-HAT Activity

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Takahiro Katagiri ◽  
Yoichi Sunagawa ◽  
Masafumi Funamoto ◽  
Yasufumi Katanasaka ◽  
Yusuke Miyazaki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Transcription ◽  
Left Ventricular ◽  
Vehicle Group ◽  
Cardiomyocyte Hypertrophy ◽  
Cell Diameter ◽  
Mrna Levels ◽  
Ecklonia Stolonifera ◽  
Hypertrophic Response ◽  
Cultured Cardiomyocytes

Introduction: Heart failure is the leading cause of death in the world. Cardiomyocyte hypertrophy is observed during the development of heart failure, suggesting that its inhibition is a potential target for the prevention and treatment of heart failure. In this study, we screened a natural compound library using cultured cardiomyocytes and found that Ecklonia stolonifera Okamura extract (ESE) suppressed cardiomyocyte hypertrophy. ESE, a perennial brown alga, has been reported to have various bioactive effects, such as antioxidant and anti-inflammatory activity, but its effect on heart failure is still unclear. Therefore, we investigated whether ESE has an inhibitory effect on cardiomyocyte hypertrophic response and on the progression of heart failure in post-myocardial infarction (MI) rats. Methods and Results: First, primary cultured cardiomyocytes from neonatal rats were treated with ESE and then stimulated with phenylephrine (PE) for 48 hours. ESE (1000 μg/mL) significantly suppressed PE-induced increases in cardiomyocyte surface area, hypertrophic response gene transcription, and acetylation of histone H3K9. An in vitro p300-HAT assay indicated that ESE directly inhibited p300-HAT activity (IC50: 505 μg/mL). Next, one week after the ligation of the left anterior descending artery, rats with moderate MI (left ventricular fractioning shorting (LVFS) <40%) were randomly assigned to three groups: vehicle (saline) (n=9), ESE (0.3 g/kg) (n=10), or ESE (1 g/kg) (n=10). Daily oral administration was repeated for 8 weeks. After treatment, LVFS was significantly higher in the ESE (1 g/kg) group (23.3 ± 0.7%, p<0.05) than in the vehicle group (16.6 ± 1.3%). Next, the hearts were isolated and histological analysis, evaluation of gene transcription, and measurement of histone H3K9 acetylation. were performed. ESE treatment significantly suppressed MI-induced increases both in myocardial cell diameter and in the mRNA levels of hypertrophic response genes. ESE also inhibited MI-induced perivascular fibrosis and the acetylation of histone H3K9. Conclusion: These results suggest that ESE suppresses both hypertrophic responses in cardiomyocytes and the development of heart failure by inhibiting p300-HAT activity. Further studies are needed to clarify the effectiveness of ESE for heart failure therapy.

Abstract P410: A Novel Curcumin Formulation, ASD-cur Suppressed Heart Failure After Myocardial Infarction In Rats

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Hidemichi Takai ◽  
Tatsuya Morimoto
Keyword(s):  
Heart Failure ◽  
Plasma Concentration ◽  
Cardiac Fibrosis ◽  
Myocardial Cell ◽  
Left Ventricular ◽  
Cell Diameter ◽  
Maximum Plasma ◽  
Mrna Levels ◽  
Time Curve ◽  
Sd Rats

Introduction: Curcumin prevents the development of heart failure and is a potential treatment for heart failure. Although curcumin is known to be safe, its therapeutic efficiency is limited due to its low bioavailability. To overcome this problem, we developed ASD-Cur, an amorphous formulation of curcumin. In this study, we investigated the effect of ASD-Cur and compared it with Theracurmin ® , a colloidal submicron dispersion of curcumin. Methods: Male SD rats were orally administrated with ASD-Cur or Theracurmin ® (10 mg/kg curcumin). The plasma levels of curcumin were measured at 0.25, 0.5, 1, 2, 4 and 6 hours after administration. Twelve healthy volunteers, who had provided written informed consent, were administrated with ASD-Cur and Theracurmin ® containing 30 mg curcumin, and plasma curcumin concentrations were determined at 0.5, 1, 2, 4, and 8 hours. Next, male SD rats were subjected to MI or sham surgery. One week after surgery, the MI rats were randomly assigned to 4 groups: vehicle, ASD-Cur (0.2 mg/kg curcumin) or Theracurmin ® (0.2 or 0.5 mg/kg curcumin). Oral administration of these compounds was repeated for 6 weeks. After echocardiographic examinations, myocardial cell diameter, perivascular fibrosis, mRNA levels, and the acetylation of histone H3K9 were measured. Results: After administration in rats, the area under the plasma concentration-time curve ( AUC 0-6h ) and the maximum plasma concentration ( C max ) of ASD-Cur were 3.7-fold and 9.6-fold higher than those of Theracurmin ® , respectively. The AUC 0-8h and C max of ASD-Cur in humans were 3.4-fold and 5.4-fold higher than those of Theracurmin ® , respectively. Echocardiographic analysis showed that 0.2 mg/kg ASD-Cur and 0.5 mg/kg Theracurmin ® significantly improved the MI-induced deterioration of FS and left ventricular hypertrophy to the same extent. Both treatments significantly suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers and cardiac fibrosis, and acetylation of histone H3K9 to the same extent. Conclusion: These findings indicated that ASD-Cur has greater bioavailability than Theracurmin ® , and could exhibit greater therapeutic potency towards for MI-induced heart failure at a lower dose.

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.

Heart failure due to chronic experimental aortic regurgitation

1994 ◽  
Vol 267 (2) ◽  
pp. H556-H562 ◽  
Author(s):  
N. M. Magid ◽  
G. Opio ◽  
D. C. Wallerson ◽  
M. S. Young ◽  
J. S. Borer
Keyword(s):  
Heart Failure ◽  
Aortic Regurgitation ◽  
Systolic Dysfunction ◽  
Disease Process ◽  
Experimental Models ◽  
Left Ventricular ◽  
Sham Operation ◽  
Systolic Performance ◽  
Baseline Values ◽  
Chronic Aortic Regurgitation

Previously reported experimental models of aortic regurgitation generally have manifested normal systolic performance and have not developed heart failure [Magid et al. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H226–H233, 1992]. To determine whether more severe chronic experimental aortic regurgitation would generate systolic malperformance, heart failure, and emulate the human disease process, 11 New Zealand White rabbits underwent surgical induction of aortic regurgitation and 5 control animals underwent sham operation. Doppler echocardiography was performed serially for up to 3 yr, and pathological studies were performed at necropsy. Left ventricular internal dimension at end diastole increased 80% (P < 0.00002) and left ventricular weight increased 250% (P < 0.0002) in aortic regurgitant rabbits (regurgitant fraction 52 +/- 13%) compared with baseline values. Six of 11 aortic regurgitant animals died with pathological evidence of congestive heart failure at 1.5 +/- 0.8 yr postoperatively; 2 of these developed severe systolic malperformance, manifest as fractional shortenings of 15 and 19% at 1.6 and 1.7 yr, respectively. Five of 11 aortic regurgitant animals survived until killed at 2.9 +/- 0.1 yr. Thus moderate-to-severe chronic aortic regurgitation in rabbits frequently results in heart failure and systolic dysfunction and may usefully model chronic aortic regurgitation and heart failure in humans.

scholarly journals Right versus left ventricular remodeling in heart failure due to chronic volume overload: pressure-volume and proteome analysis

2021 ◽  
Author(s):  
Tereza Havlenova ◽  
Petra Skaroupkova ◽  
Matus Miklovic ◽  
Matej Behounek ◽  
Martin Chmel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Systolic Dysfunction ◽  
Volume Overload ◽  
Left Ventricular ◽  
Cytoskeletal Proteins ◽  
Sham Operation ◽  
Stroke Work ◽  
Specific Regulation

Abstract Mechanisms of right ventricular (RV) dysfunction in heart failure (HF) are poorly understood. RV response to volume overload (VO), a common contributing factor to HF, is rarely studied. The goal was to identify interventricular differences in response to chronic VO. Rats underwent aorto-caval fistula (ACF)/sham operation to induce VO. After 24 weeks, RV and left ventricular (LV) functions, gene expression and proteomics were studied. ACF led to biventricular dilatation, systolic dysfunction and hypertrophy affecting relatively more RV. Increased RV afterload contributed to larger RV stroke work increment compared to LV. Both ACF ventricles displayed upregulation of genes of myocardial stress and metabolism. Most proteins reacted to VO in a similar direction in both ventricles, yet the expression changes were more pronounced in RV. The most upregulated were extracellular matrix (POSTN, NRAP, TGM2, CKAP4), cell adhesion (NCAM, NRAP, XIRP2) and cytoskeletal proteins (FHL1, CSRP3) and enzymes of carbohydrate (PKM) or norepinephrine (MAOA) metabolism. Downregulated were MYH6 and FAO enzymes. Therefore, when exposed to identical VO, both ventricles display similar upregulation of stress and metabolic markers. RV reacts to ACF relatively more than LV due to concomitant pulmonary hypertension. No evidence supports RV chamber-specific regulation of protein expression in response to VO.

scholarly journals Toxicity of cancer therapy: what the cardiologist needs to know about angiogenesis inhibitors

Heart ◽  
2018 ◽  
Vol 104 (24) ◽  
pp. 1995-2002 ◽  
Author(s):  
Stephen J H Dobbin ◽  
Alan C Cameron ◽  
Mark C Petrie ◽  
Robert J Jones ◽  
Rhian M Touyz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Cancer Therapy ◽  
Therapeutic Potential ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Dysfunction ◽  
Blood Pressure Measurement ◽  
Left Ventricular ◽  
National Guidelines ◽  
Wide Range

Clinical outcomes for patients with a wide range of malignancies have improved substantially over the last two decades. Tyrosine kinase inhibitors (TKIs) are potent signalling cascade inhibitors and have been responsible for significant advances in cancer therapy. By inhibiting vascular endothelial growth factor receptor (VEGFR)-mediated tumour blood vessel growth, VEGFR-TKIs have become a mainstay of treatment for a number of solid malignancies. However, the incidence of VEGFR-TKI-associated cardiovascular toxicity is substantial and previously under-recognised. Almost all patients have an acute rise in blood pressure, and the majority develop hypertension. They are associated with the development of left ventricular systolic dysfunction (LVSD), heart failure and myocardial ischaemia and can have effects on myocardial repolarisation. Attention should be given to rigorous baseline assessment of patients prior to commencing VEGFR-TKIs, with careful consideration of baseline cardiovascular risk factors. Baseline blood pressure measurement, ECG and cardiac imaging should be performed routinely. Hypertension management currently follows national guidelines, but there may be a future role forendothelin-1 antagonism in the prevention or treatment of VEGFR-TKI-associated hypertension. VEGFR-TKI-associated LVSD appears to be independent of dose and is reversible. Patients who develop LVSD and heart failure should be managed with conventional heart failure therapies, but the role of prophylactic therapy is yet to be defined. Serial monitoring of left ventricular function and QT interval require better standardisation and coordinated care. Management of these complex patients requires collaborative, cardio-oncology care to allow the true therapeutic potential from cancer treatment while minimising competing cardiovascular effects.

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