scholarly journals Na+/H+ exchanger isoform 1-induced osteopontin expression facilitates cardiac hypertrophy through p90 ribosomal S6 kinase

2018 ◽  
Vol 50 (5) ◽  
pp. 332-342 ◽  
Author(s):  
Nabeel Abdulrahman ◽  
Beatrice Jaspard-Vinassa ◽  
Larry Fliegel ◽  
Aayesha Jabeen ◽  
Sadaf Riaz ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Internal Diameter ◽  
S6 Kinase ◽  
Cardiac Phenotype ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

Cardiovascular diseases are the leading cause of death worldwide. One in three cases of heart failure is due to dilated cardiomyopathy. The Na+/H+ exchanger isoform 1 (NHE1), a multifunctional protein and the key pH regulator in the heart, has been demonstrated to be increased in this condition. We have previously demonstrated that elevated NHE1 activity induced cardiac hypertrophy in vivo. Furthermore, the overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an upregulation of myocardial osteopontin (OPN) expression. To determine the role of OPN in inducing NHE1-mediated cardiomyocyte hypertrophy, double transgenic mice expressing active NHE1 and OPN knockout were generated and assessed by echocardiography and the cardiac phenotype. Our studies showed that hearts expressing active NHE1 exhibited cardiac remodeling indicated by increased systolic and diastolic left ventricular internal diameter and increased ventricular volume. Moreover, these hearts demonstrated impaired function with decreased fractional shortening and ejection fraction. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA was upregulated, and there was an increase in heart cell cross-sectional area confirming the cardiac hypertrophic effect. Moreover, NHE1 transgenic mice also showed increased collagen deposition, upregulation of CD44 and phosphorylation of p90 ribosomal s6 kinase (RSK), effects that were regressed in OPN knockout mice. In conclusion, we developed an interesting comparative model of active NHE1 transgenic mouse lines which express a dilated hypertrophic phenotype expressing CD44 and phosphorylated RSK, effects which were regressed in absence of OPN.

scholarly journals p90 ribosomal S6 kinase 3 contributes to cardiac insufficiency in α-tropomyosin Glu180Gly transgenic mice

2013 ◽  
Vol 305 (7) ◽  
pp. H1010-H1019 ◽  
Author(s):  
Catherine L. Passariello ◽  
Marjorie Gayanilo ◽  
Michael D. Kritzer ◽  
Hrishikesh Thakur ◽  
Zoharit Cozacov ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Interstitial Fibrosis ◽  
Cardiac Insufficiency ◽  
S6 Kinase ◽  
Transgenic Expression ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

Myocardial interstitial fibrosis is an important contributor to the development of heart failure. Type 3 p90 ribosomal S6 kinase (RSK3) was recently shown to be required for concentric myocyte hypertrophy under in vivo pathological conditions. However, the role of RSK family members in myocardial fibrosis remains uninvestigated. Transgenic expression of α-tropomyosin containing a Glu180Gly mutation (TM180) in mice of a mixed C57BL/6:FVB/N background induces a cardiomyopathy characterized by a small left ventricle, interstitial fibrosis, and diminished systolic and diastolic function. Using this mouse model, we now show that RSK3 is required for the induction of interstitial fibrosis in vivo. TM180 transgenic mice were crossed to RSK3 constitutive knockout ( RSK3−/−) mice. Although RSK3 knockout did not affect myocyte growth, the decreased cardiac function and mild pulmonary edema associated with the TM180 transgene were attenuated by RSK3 knockout. The improved cardiac function was consistent with reduced interstitial fibrosis in the TM180; RSK3−/− mice as shown by histology and gene expression analysis, including the decreased expression of collagens. The specific inhibition of RSK3 should be considered as a potential novel therapeutic strategy for improving cardiac function and the prevention of sudden cardiac death in diseases in which interstitial fibrosis contributes to the development of heart failure.

scholarly journals Na+/H+ Exchanger Isoform 1 Induced Cardiomyocyte Hypertrophy Involves Activation of p90 Ribosomal S6 Kinase

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0122230 ◽  
Author(s):  
Maiy Jaballah ◽  
Iman A. Mohamed ◽  
Bayan Alemrayat ◽  
Fatima Al-Sulaiti ◽  
Mohamed Mlih ◽  
...  
Keyword(s):  
Cardiomyocyte Hypertrophy ◽  
S6 Kinase ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

Abstract 190: Disruption of P90 Ribosomal S6 Kinase Binding 3 to Muscle A-kinase Anchoring Protein In Vivo Via Adeno-associated Virus Expression of a Competing Peptide Attenuates Pressure Overload-induced Cardiac Hypertrophy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
CATHERINE L PASSARIELLO ◽  
Michael D Kritzer ◽  
Hrishikesh Thakur ◽  
Michael Sanders ◽  
Jinliang Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Myocyte ◽  
Troponin T ◽  
Pressure Overload ◽  
Compensatory Response ◽  
S6 Kinase ◽  
Anchoring Protein ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

RATIONALE: Cardiac myocyte hypertrophy is the main compensatory response to chronic stress in the heart. p90 ribosomal S6 kinase (RSK) family members are effectors for extracellular signal-regulated kinases that induce myocyte growth. RSK3 contains a unique N-terminal domain that mediates RSK3 binding to the muscle A-kinase anchoring protein (mAKAPβ) scaffold. We have previously published that disruption of RSK3-mAKAPβ complexes using a competing peptide inhibited the phenylephrine-induced hypertrophy of neonatal ventricular myocytes in vitro. In vivo, RSK3 gene deletion in mice attenuated the concentric cardiac hypertrophy induced by pressure overload. We hypothesize that RSK3 anchoring to mAKAPβ in myocytes is required for cardiac hypertrophy in vivo. METHODS AND RESULTS: Adeno-associated viruses (AAV) are gene therapy vectors in development for the treatment of human diseases owing to their nonpathogenic capability for transducing non-dividing cells and their long-term transgene expression. We have used a recombinant AAV2/9 vector to express a mAKAPβ RSK3-binding domain (RBD)-GFP fusion protein under the control of the cardiac myocyte-specific cardiac troponin T promoter. 3 day-old C57BL/6 mice were injected intraperitoneally with either AAV-RBD-GFP or AAV-GFP control virus. At 8 weeks of age mice were subjected to transverse aortic constriction to induce pressure overload (TAC) for two weeks. Cardiac hypertrophy was attenuated in mice injected with the AAV-RBD-GFP virus (biventricular weight indexed to tibial length (mg/mm): 7.7, 8.6, and 9.2 for AAV-RBD, AAV-GFP and non-injected TAC cohorts, respectively; p<0.05 vs. both controls). Echocardiography both corroborated the inhibition of hypertrophy and revealed no deleterious effect on cardiac function attributable to the AAV-RBD-GFP vector. CONCLUSIONS: Anchored RSK3 regulates pathologic myocyte growth. AAV can successfully deliver a competing peptide inhibiting pathological hypertrophy and should be investigated further as a prevention and/or treatment for heart failure.

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 An Intracellular Calcium Signal Activates p70 but Not p90 Ribosomal S6 Kinase in Liver Epithelial Cells

1997 ◽  
Vol 272 (3) ◽  
pp. 1920-1928 ◽  
Author(s):  
Lee M. Graves ◽  
Yaqin He ◽  
John Lambert ◽  
Deborah Hunter ◽  
Xiong Li ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intracellular Calcium ◽  
Calcium Signal ◽  
S6 Kinase ◽  
Liver Epithelial Cells ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

Dendropanax morbifera Prevents Cardiomyocyte Hypertrophy by Inhibiting the Sp1/GATA4 Pathway

2018 ◽  
Vol 46 (05) ◽  
pp. 1021-1044 ◽  
Author(s):  
Simei Sun ◽  
Tianyi Li ◽  
Li Jin ◽  
Zhe Hao Piao ◽  
Bin Liu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Mapk Signaling ◽  
Cardiomyocyte Hypertrophy ◽  
Marker Genes ◽  
H9c2 Cell ◽  
Small Interfering Rnas ◽  
Dihydroxybenzoic Acid ◽  
Anticancer Activities ◽  
Dendropanax Morbifera

An extract of Dendropanax morbifera branch exerts antioxidant, anti-inflammatory, antithrombotic, and anticancer activities. The purpose of this study was to investigate the effect of the extract in isoproterenol-induced cardiac hypertrophy. Phalloidin staining showed that treatment with the extract dramatically prevents isoproterenol-induced H9c2 cell enlargement and the expression of cardiac hypertrophic marker genes, including atrial natriuretic peptide (ANP) and B-type brain natriuretic peptide (BNP). Further, pretreatment with the extract decreased isoproterenol-induced GATA4 and Sp1 expression in H9c2 cells. Overexpression of Sp1 induced the expression of GATA4. The forced expression of Sp1 or its downstream target GATA4, as well as the co-transfection of Sp1 and GATA4 increased the expression of ANP, which was decreased by treatment with the extract. To further elucidate the regulation of the Sp1/GATA4-mediated expression of ANP, knockdown experiments were performed. Transfection with small interfering RNAs (siRNAs) for Sp1 or GATA4 decreased ANP expression. The extract did not further inhibit the expression of ANP reduced by the transfection of GATA4 siRNA. Sp1 knockdown did not affect the expression of ANP that was induced by the overexpression of GATA4; however, GATA4 knockdown abolished the expression of ANP that had been induced by Sp1 overexpression. The extract treatment also attenuated the isoproterenol-induced activation of p38 MAPK, ERK1/2, and JNK1. Hesperidin, catechin, 2,5-dihydroxybenzoic acid, and salicylic acid are the main phenolic compounds present in the extract as observed by high performance liquid chromatography. Hesperidin and 2,5-dihydroxybenzoic acid attenuated isoproterenol-induced cardiac hypertrophy. These findings suggest that the D. morbifera branch extract prevents cardiac hypertrophy by downregulating the activation of Sp1/GATA4 and MAPK signaling pathways.

Abstract 080: Eya4 Induces Hypertrophy Via Regulation Of p27kip1

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Tatjana Williams ◽  
Moritz Hundertmark ◽  
Peter Nordbeck ◽  
Sabine Voll ◽  
Melanie Muehlfelder ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Dominant Negative ◽  
Heart Weight ◽  
Dominant Negative Effect ◽  
Mutant Form ◽  
Cardiac Phenotype ◽  
Truncating Mutation

Introduction: E193, a truncating mutation in the transcription cofactor Eyes absent 4 (Eya4) causes hearing impairment followed by heart failure. Here we identified the Eya4 dependent molecular mechanisms leading to the cardiac phenotype in the E193 mutation. Methods and Results: First we showed in vitro that the cyclin-dependent kinase inhibitor protein p27kip1 is a direct target of Eya4/Six1 and is suppressed upon Eya4 overexpression, whereas E193 has a dominant negative effect, releasing Eya4 mediated suppression of p27. We next generated transgenic mice with cardiac specific constitutive overexpression of full-length Eya4 or the mutant form E193. While E193 transgenic mice developed age-dependent DCM, Eya4 mice displayed cardiac hypertrophy already under basal conditions as judged by increases in heart weight and cardiomyocyte cross-sectional areas along with increases in myocardial dimension and mass. These two distinct cardiac phenotypes were even more aggravated upon pressure overload suggesting Eya4 is a regulator of cardiac hypertrophy. We also observed that the activity of Casein Kinase 2-α and the phosphorylation status of HDAC2 were significantly upregulated in the Eya4 transgenic mice, while they were significantly reduced in E193 mice, under baseline conditions and pressure overload. We were also able to identify a new human mutation (E215) with a phenotype comparable to the one seen in E193 patients. Conclusion: Our results implicate that Eya4/Six1 regulates cardiac hypertrophic reactions via p27/CK2-α/HDAC2 and indicate that truncating mutations in Eya4 interfere with this newly established signalling pathway.

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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