scholarly journals Granule cargo release from bone marrow-derived cells sustains cardiac hypertrophy

2014 ◽  
Vol 307 (10) ◽  
pp. H1529-H1538 ◽  
Author(s):  
Fanmuyi Yang ◽  
Anping Dong ◽  
Jasimuddin Ahamed ◽  
Manjula Sunkara ◽  
Susan S. Smyth
Keyword(s):  
Bone Marrow ◽  
Cardiac Hypertrophy ◽  
Inflammatory Responses ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Enzyme Linked Immunosorbent Assay ◽  
Late Time ◽  
Chimeric Mice ◽  
Bone Marrow Derived Cells ◽  
Granule Secretion

Bone marrow-derived inflammatory cells, including platelets, may contribute to the progression of pressure overload-induced left ventricular hypertrophy (LVH). However, the underlying mechanisms for this are still unclear. One potential mechanism is through release of granule cargo. Unc13-d Jinx (Jinx) mice, which lack Munc13-4, a limiting factor in vesicular priming and fusion, have granule secretion defects in a variety of hematopoietic cells, including platelets. In the current study, we investigated the role of granule secretion in the development of LVH and cardiac remodeling using chimeric mice specifically lacking Munc13-4 in marrow-derived cells. Pressure overload was elicited by transverse aortic constriction (TAC). Chimeric mice were created by bone marrow transplantation. Echocardiography, histology staining, immunohistochemistry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were used to study LVH progression and inflammatory responses. Wild-type (WT) mice that were transplanted with WT bone marrow (WT→WT) and WT mice that received Jinx bone marrow (Jinx→WT) developed LVH and a classic fetal reprogramming response early (7 days) after TAC. However, at late times (5 wk), mice lacking Munc13-4 in bone marrow-derived cells (Jinx→WT) failed to sustain the cardiac hypertrophy observed in WT chimeric mice. No difference in cardiac fibrosis was observed at early or late time points. Reinjection of WT platelets or platelet releasate partially restored cardiac hypertrophy in Jinx chimeric mice. These results suggest that sustained LVH in the setting of pressure overload depends on one or more factors secreted from bone marrow-derived cells, possibly from platelets. Inhibiting granule cargo release may represent a novel target for preventing sustained LVH.

scholarly journals SPARC Production by Bone Marrow-Derived Cells Contributes to Myocardial Fibrosis in Pressure-Overload

2020 ◽  
Author(s):  
Hannah J Riley ◽  
Ryan R Kelly ◽  
An O. Van Laer ◽  
Lily S Neff ◽  
Shaoni Dasgupta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Cellular Adhesion ◽  
Left Ventricular ◽  
Human Heart Failure ◽  
Myocardial Stiffness ◽  
Cellular Adhesion Molecule ◽  
Bone Marrow Derived Cells ◽  
Sparc Expression

In human heart failure and in murine hearts with left ventricular pressure overload (LVPO), increases in fibrosis are associated with increases in stiffness. Secreted Protein Acidic and Rich in Cysteine (SPARC) is necessary for both cardiac fibrosis and increases in myocardial stiffness in response to LVPO, however cellular sources of cardiac SPARC are incompletely defined. Irradiation and bone marrow transfer were undertaken to test the hypothesis that SPARC expression by bone marrow-derived cells is an important mediator of fibrosis in LVPO. In recipient SPARC-null mice transplanted with donor wild-type (WT) bone marrow and subjected to LVPO, levels of fibrosis similar to that of WT hearts were found despite the lack of SPARC expression by resident cells. In recipient WT mice with donor SPARC-null bone marrow, significantly less fibrosis versus that of WT was found despite the expression of SPARC by resident cells. Increases in myocardial stiffness followed a similar pattern to that of collagen deposition. Myocardial macrophages were significantly reduced in SPARC-null mice with LVPO versus that of WT hearts. Recipient SPARC-null mice transplanted with donor WT bone marrow exhibited an increase in cardiac macrophages versus that of SPARC-null LVPO and donor WT mice with recipient SPARC-null bone marrow. Expression of Vascular Cellular Adhesion Molecule (VCAM) was found to be in increased in all groups with LVPO with the exception of WT mice. In conclusion, SPARC expression by bone marrow-derived cells was critical for fibrotic deposition of collagen and influenced the expansion of myocardial macrophages in response to LVPO.

Abstract 228: Secretion of Bone Marrow--Derived Cells Contributes to Pressure-Overload--Induced Left Ventricular Hypertrophy

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Fanmuyi Yang ◽  
Anping Dong ◽  
Susan Smyth
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Cardiac Fibrosis ◽  
Marrow Cell ◽  
Pressure Overload ◽  
Inflammatory Cells ◽  
Left Ventricular ◽  
Limiting Factor ◽  
Single Point Mutation ◽  
Bone Marrow Derived Cells

Bone marrow derived cells, especially inflammatory cells, may contribute to the pathological progression of pressure overload induced left ventricular (LV) hypertrophy and cardiac fibrosis. Previously, we reported that inflammatory cell accumulation and upregulation of cytokines in hearts of mice that had undergone transverse aortic constriction (TAC) surgery predicted later cardiac hypertrophic and fibrotic remodeling. However, the underlining mechanisms are still not clear. One potential mechanism for inflammatory cells to modulate their environment and affect surrounding cells is through release of cargo stored in granules. Jinx mice - which contain a single point mutation in Unc13d encoding the Munc13-4 protein, a limiting factor in vesicular priming and fusion - have defects in granular secretion in hematopoietic cells, such as platelets, NK cells, and neutrophils. In the current study, we investigated the role of bone marrow cell granule secretion in TAC-induced LV remodeling by creating with bone marrow transplantation chimeric mice specifically lacking Munc13-4 in marrow derived cells. Both wild-type mice (WT) that were transplanted with WT bone marrow and WT mice that received Jinx bone marrow developed LVH and a classic fetal reprogramming response early (7 days) after TAC. However, at later times (5 weeks), mice lacking Munc13-4 in bone marrow-derived cells failed to sustain the cardiac hypertrophy observed in mice with WT bone marrow. No difference in cardiac fibrosis was observed at early or late times. These results suggest that sustained LVH in the setting of pressure overload depends on factor(s) secreted from bone marrow-derived cells, likely from either platelets, NK cells and/or neutrophils. Inhibiting granule cargo release may represent a novel therapeutic target to prevent the development of LVH.

scholarly journals Bone Marrow–Derived Cells Are Involved in the Pathogenesis of Cardiac Hypertrophy in Response to Pressure Overload

Circulation ◽  
2007 ◽  
Vol 116 (10) ◽  
pp. 1176-1184 ◽  
Author(s):  
Jin Endo ◽  
Motoaki Sano ◽  
Jun Fujita ◽  
Kentaro Hayashida ◽  
Shinsuke Yuasa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Bone Marrow Derived Cells

Myeloid-Derived Growth Factor Protects Against Pressure Overload-Induced Heart Failure by Preserving Sarco/Endoplasmic Reticulum Ca 2+ -ATPase Expression in Cardiomyocytes

Circulation ◽  
2021 ◽  
Author(s):  
Mortimer Korf-Klingebiel ◽  
Marc R. Reboll ◽  
Felix Polten ◽  
Natalie Weber ◽  
Felix Jäckle ◽  
...  
Keyword(s):  
Heart Failure ◽  
Bone Marrow ◽  
Endoplasmic Reticulum ◽  
Growth Factor ◽  
Plasma Concentrations ◽  
Pressure Overload ◽  
Inflammatory Cells ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Wild Type

Background: Inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Inflammatory cells secrete myeloid-derived growth factor (MYDGF) to promote tissue repair after acute myocardial infarction. We hypothesized that MYDGF has a role in cardiac adaptation to persistent pressure overload. Methods: We defined the cellular sources and function of MYDGF in wild-type, Mydgf -deficient ( Mydgf -/- ), and Mydgf bone marrow-chimeric or bone marrow-conditional transgenic mice with pressure overload-induced heart failure after transverse aortic constriction surgery. We measured MYDGF plasma concentrations by targeted liquid chromatography-mass spectrometry. We identified MYDGF signaling targets by phosphoproteomics and substrate-based kinase activity inference. We recorded Ca 2+ transients and sarcomere contractions in isolated cardiomyocytes. Additionally, we explored the therapeutic potential of recombinant MYDGF. Results: MYDGF protein abundance increased in the left ventricular (LV) myocardium and in blood plasma of pressure-overloaded mice. Patients with severe aortic stenosis also had elevated MYDGF plasma concentrations, which declined after transcatheter aortic valve implantation. Monocytes and macrophages emerged as the main MYDGF sources in the pressure-overloaded murine heart. While Mydgf -/- mice had no apparent phenotype at baseline, they developed more severe LV hypertrophy and contractile dysfunction during pressure overload than wild-type mice. Conversely, conditional transgenic overexpression of MYDGF in bone marrow-derived inflammatory cells attenuated pressure overload-induced hypertrophy and dysfunction. Mechanistically, MYDGF inhibited G protein coupled receptor agonist-induced hypertrophy and augmented sarco/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a) expression in cultured neonatal rat cardiomyocytes by enhancing PIM1 serine/threonine kinase expression and activity. Along this line, cardiomyocytes from pressure-overloaded Mydgf -/- mice displayed reduced PIM1 and SERCA2a expression, greater hypertrophy, and impaired Ca 2+ cycling and sarcomere function compared to cardiomyocytes from pressure-overloaded wild-type mice. Transplanting Mydgf -/- mice with wild-type bone marrow cells augmented cardiac PIM1 and SERCA2a levels and ameliorated pressure overload-induced hypertrophy and dysfunction. Pressure-overloaded Mydgf -/- mice were similarly rescued by adenoviral Serca2a gene transfer. Treating pressure-overloaded wild-type mice subcutaneously with recombinant MYDGF enhanced SERCA2a expression, attenuated LV hypertrophy and dysfunction, and improved survival. Conclusions: These findings establish a MYDGF-based adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against pressure overload-induced heart failure.

Role of sarcoplasmic reticulum in loss of load-sensitive relaxation in pressure overload cardiac hypertrophy

1994 ◽  
Vol 266 (1) ◽  
pp. H68-H78 ◽  
Author(s):  
C. R. Cory ◽  
R. W. Grange ◽  
M. E. Houston
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Hypertrophy ◽  
Atpase Activity ◽  
Pressure Overload ◽  
Fold Increase ◽  
Left Ventricular ◽  
Isometric Tension ◽  
Tension Development ◽  
Sequestration Potential

The loss of load-sensitive relaxation observed in the pressure-overloaded heart may reflect a strategy of slowed cytosolic Ca2+ uptake to yield a prolongation of the active state of the muscle and a decrease in cellular energy expenditure. A decrease in the potential of the sarcoplasmic reticulum (SR) to resequester cytosolic Ca2+ during diastole could contribute to this attenuated load sensitivity. To test this hypothesis, both in vitro mechanical function of anterior papillary muscles and the SR Ca2+ sequestration potential of female guinea pig left ventricle were compared in cardiac hypertrophy (Hyp) and sham-operated (Sham) groups. Twenty-one days of pressure overload induced by coarctation of the suprarenal, subdiaphragmatic aorta resulted in a 36% increase in left ventricular mass in the Hyp. Peak isometric tension, the rate of isometric tension development, and the maximal rates of isometric and isotonic relaxation were significantly reduced in Hyp. Load-sensitive relaxation were significantly reduced in Hyp. Load-sensitive relaxation quantified by the ratio of a rapid loading to unloading force step in isotonically contracting papillary muscle was reduced 50% in Hyp muscles. Maximum activity of SR Ca(2+)-adenosinetriphosphatase (ATPase) measured under optimal conditions (37 degrees C; saturating Ca2+) was unaltered, but at low free Ca2+ concentrations (0.65 microM), it was decreased by 43% of the Sham response. Bivariate regression analysis revealed a significant (r = 0.84; P = 0.009) relationship between the decrease in SR Ca(2+)-ATPase activity and the loss of load-sensitive relaxation after aortic coarctation. Stimulation of the SR Ca(2+)-ATPase by the catalytic subunit of adenosine 3',5'-cyclic monophosphate-dependent protein kinase resulted in a 2.6-fold increase for Sham but only a 1.6-fold increase for Hyp. Semiquantitative Western blot radioimmunoassays revealed that the changes in SR Ca(2+)-ATPase activity were not due to decreases in the content of the Ca(2+)-ATPase protein or phospholamban. Our data directly implicate a role for decreased SR function in attenuated load sensitivity. A purposeful downregulation of SR Ca2+ uptake likely results from a qualitative rather than a quantitative change in the ATPase and possibly one of its key regulators, phospholamban.

scholarly journals 4-Methylumbelliferone Attenuates Macrophage Invasion and Myocardial Remodeling in Pressure-Overloaded Mouse Hearts

Hypertension ◽  
2021 ◽  
Author(s):  
Katarzyna Hackert ◽  
Susanne Homann ◽  
Shakila Mir ◽  
Arne Beran ◽  
Simone Gorreßen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hyaluronic Acid ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Pressure Overload ◽  
Myocardial Damage ◽  
Left Ventricular ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Cardiac Wall

Cardiac wall stress induces local and systemic inflammatory responses that are increasingly recognized as key modulators of extracellular matrix remodeling. Hyaluronic acid interacts with immune cells and mesenchymal cells thereby modulating profibrotic signals. Here we tested the hypothesis that 4-methylumbelliferone (4-MU), an inhibitor of hyaluronic acid synthesis, would attenuate inflammation and extracellular matrix remodeling of pressure-overloaded myocardium in C57BL/6J male mice fed with 4-MU and subjected to TAC (transverse aortic constriction) surgery. Flow cytometry of immune cells showed TAC-induced leukocytosis due to an increase of neutrophils and monocytes. 4-MU strongly attenuated both circulating and cardiac leukocyte numbers 3 days after TAC. In the hearts, 4-MU reduced the number of CCR2 − resident macrophages. At later time points, 4-MU also prevented the infiltration of heart tissue by bone marrow-derived circulating monocytes leading to reduced cardiac macrophage counts even 7 weeks after TAC. The long-term attenuation of macrophage-driven inflammation was associated with less myocardial fibrosis in 4-MU-treated compared with untreated mice. Unexpectedly, 4-MU also reduced the development of left ventricular hypertrophy and increased cardiac output after TAC without affecting blood pressure. The data demonstrate that 4-MU reduces both resident and invading cardiac macrophages and may be a promising agent to alleviate pressure-overload induced myocardial damage.

scholarly journals Leonurine Attenuates Pressure-Overload Cardiac Hypertrophy Induced By Abdominal Aortic Constriction In Rats

2021 ◽  
Author(s):  
Ding Xiaoli ◽  
Yuan Qingqing ◽  
Qian Haibing
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Ang Ii ◽  
Aortic Constriction ◽  
Qrt Pcr ◽  
Abdominal Aortic

Abstract Background: Myocardial hypertrophy occurs in many cardiovascular diseases. Leonurine (Leo) is commonly used for cardiovascular and cerebrovascular diseases. However, whether it can prevent cardiac hypertrophy is not known. The aim of this study was to investigate the effect and mechanism of Leonurine (Leo) against pressure-overload cardiac hypertrophy induced by abdominal aortic constriction (AAC) in rats. Methods: To answer this question, we prove it in the following way: Cardiac function was evaluated by hemodynamic; the left ventricle enlargement was measured by heart weight index (HWI) and left ventricular mass index (LVWI); myocardial tissue changes and myocardial cell diameter (MD) were determined by Hematoxylin and eosin (HE) staining; theβ-myosin heavy chain(β-MHC)and atrial natriuretic factor (ANF), which are recognized as a marker of cardiac hypertrophy, were determined by Real-time quantitative PCR (qRT-PCR), then another gene phospholipase C (PLC), inositol triphosphate (IP3), which associated with RAS were determined by Western blot(WB). angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R) were determined by ELISA, WB and qRT-PCR methods. Finally, we measured the level of Ca2+ by microplate method and the protooncogene c-fos and c-myc mRNA in left ventricular myocardium by qRT-PCR.Results: Compare with control group, Leonurine can improve systolic dysfunction; inhibit the increase of left cardiac; inhibit myocardial cells were abnormally large and restrain the changes of cardiac histopathology; decrease the expression of β-MHC, ANF, Ang II, AT1R, c-fos and c-myc mRNA and the protein levels of PLC, IP3, AngII and AT1R in left ventricular myocardium, in addition, the content of Ca2+ also decrease. Conclusion: Therefore, Leonurine can inhibit cardiac hypertrophy induced by AAC and its effects may be associated with RAS.

Abstract 353: Bone Marrow Fibroblast Progenitor Cell-derived Exosomes Activate Resident Fibroblast and Augment Pressure Overload Induced Cardiac Fibrosis in IL10KO Mice

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Suresh K Verma ◽  
Venkata N Girikipathi ◽  
Maria Cimini ◽  
Zhongjian Cheng ◽  
Moshin Khan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cardiac Fibrosis ◽  
Culture Media ◽  
Critical Role ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiac Fibroblast ◽  
Paracrine Factors ◽  
Fibroblast Activation ◽  
Resident Fibroblast

Background: Activated fibroblasts (myoFBs) play critical role in cardiac fibrosis, however, their origin in diseased heart remains uncertain. Previous studies suggest the contribution of bone marrow fibroblasts progenitor cells (FPC) in pressure overload (PO)-induced cardiac fibrosis and inflammation acts as catalyst in this process. Recently others and we have shown that paracrine mediators packaged in exosomes play important role in cardiac pathophysiology. Thus, we hypothesized that exosome-derived from IL10KO-FPC augments PO-induced resident cardiac fibroblast activation and therefore, aggravate cardiac fibrosis. Methods and Results: Cardiac fibrosis was induced in Wild-type (WT) and IL10-knockout (IL10KO) mice by transverse aortic constriction (TAC). TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in IL10KO mice. PO-enhanced FPC (Prominin1 + cells) mobilization and homing in IL10KO mice compared to WT mice. To establish the IL10KO-FPC paracrine signaling, exosomes were isolated from WT and IL10KO BM-FPC culture media and characterized for proteins/miRNA. IL10 KO FPC-exosomes showed altered packaging of signature fibrotic miR and proteins. To explore whether FPC-exosomes modulate resident fibroblast activation, adult cardiac fibroblasts were treated with WT and IL10KO FPC-derived exosomes. IL10KO-FPC-derived exosomes exaggerate TGFβ 2 -induced activation of adult fibroblasts. These data suggest that fibrotic remodeling factors (miRs and/or proteins) packaged in IL10KO-FPC exosomes are sufficient to enhance the resident cardiac fibroblast activation and mediate cardiac fibrotic remodeling IL10 treatment significantly inhibits TGFβ 2 -induced FPC to myoFBs transition. Conclusion: Taken together, our findings suggest that paracrine factors secreted by BM-FPC augment resident cardiac fibroblast activation and fibrosis in pressure overloaded myocardium and IL10 negatively regulates this process. Ongoing investigations using molecular approaches will provide a better understanding on the mechanistic and therapeutic aspects of IL10 on PO-induced cardiac fibrosis and heart failure.

Abstract 83: Bone Marrow Derived Cells Do Not Mediate Reductions in Cholesterol, Atherosclerosis and Adiposity in Microsomal Prostaglindin E Synthase 1 Deficient Mice Fed High Fat Diets Enriched in Cholesterol

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Sarah Srodulski ◽  
Victoria L King
Keyword(s):  
Bone Marrow ◽  
Weight Gain ◽  
Marrow Cell ◽  
Atherosclerotic Lesion ◽  
Chimeric Mice ◽  
High Fat ◽  
Lesion Formation ◽  
Bone Marrow Derived Cells ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Formation

Microsomal prostaglandin E 2 synthase-1 (mPGES-1) catalyzes the conversion of COX-2 generated PGH 2 to PGE 2 and is the predominate source of PGE 2 during and inflammatory response. We and others have demonstrated that mPGES-1 deficiency attenuates atherosclerosis in mice on a mixed background. The present study investigated the effect of mPGES-1 deficiency on atherosclerosis in C57BL/6 low density lipoprotein receptor deficient (LDLr-/-) mice. mPGES-1 deficiency attenuated atherosclerosis in LDLr-/- mice fed either a low fat (LF) (P = 0.02) or high fat (HF) (P = 0.0026) diet enriched with cholesterol, or a western diet (P = 0.02) for 17 weeks. mPGES-1 deficiency attenuated weight gain and cholesterol concentrations in mice fed a western (P = 0.004 and P < 0.05; respectively) or HF diet (P = 0.01 and P = 0.012, respectively). However, body weight and cholesterol concentrations were not different in mice fed the LF diet. These data suggest that different mechanisms mediate the reduction in atherosclerosis in mPGES-1 deficient mice fed LF and HF diets. To determine if mPGES-1 deficiency in macrophages contributed to the reduction in atherosclerosis in mice fed HF diets, 4 groups of chimeric mice were generated. Four weeks post bone marrow cell transplant (BMT) mice were fed a western diet. BMT attenuated weight gain in all groups of chimeric mice; however, weight gain was not different between any of the groups. BMT decreased atherosclerotic lesion formation 10 fold in all groups of mice. Neither bone marrow cell specific deficiency of mPGES-1 (KO>WT) or mPGES-1 specific expression in bone marrow derived cells (WT>KO) had an effect on lesion formation compared to WT>WT or KO>KO mice. Cholesterol concentrations were decreased in KO>KO and WT>KO mice compared to WT>WT (P < 0.01) and KO>WT (P< 0.05) mice. These data suggest that mPGES-1 expression in bone marrow derived cells does not contribute to the development of atherosclerosis. Moreover, these data suggest that prostanoids may play a role in hepatic cholesterol homeostasis in mice fed HF diets enriched in cholesterol thereby contributing to atherosclerotic lesion formation. Moreover, these data provide further evidence that prostanoids play a role in regulating the accumulation of diet-induced adiposity.

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.

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