The calcineurin-myocyte enhancer factor 2c pathway mediates cardiac hypertrophy induced by endoplasmic reticulum stress in neonatal rat cardiomyocytes

2010 ◽  
Vol 298 (5) ◽  
pp. H1499-H1509 ◽  
Author(s):  
Zhen-Ying Zhang ◽  
Xiu-Hua Liu ◽  
Wei-Cheng Hu ◽  
Fei Rong ◽  
Xu-Dong Wu
Keyword(s):  
Endoplasmic Reticulum ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Time Dependent ◽  
Neonatal Rat ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Dependent Manner ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

Endoplasmic reticulum (ER) stress (ERS) is involved in various cardiovascular diseases. Our previous study verified that ERS took part in the development of cardiac hypertrophy; however, its mechanism is still unclear. This study aimed to investigate the roles of the calcineurin (CaN) signal pathway in hypertrophy induced by the ERS inductor thapsigargin (TG) in neonatal cardiomyocytes from Sprague-Dawley rats. Investigation of ER chaperone expression, ER staining, and calreticulin immunoflourescence were used to detect the ERS response. mRNA expression of atrial natriuretic peptide and brain natriuretic peptide, total protein synthesis rate, and cell surface area were used to evaluate cardiac hypertrophy induced by TG. TG induced a significant ERS response along with hypertrophy in a dose- and time-dependent manner in cardiomyocytes, which was verified by treatment with tunicamycin, another ERS inducer. Furthermore, TG induced a significant elevation of the intracellular Ca2+ level, CaN activation, and myocyte enhancer factor 2c (MEF2c) expression in a dose- and time-dependent manner in cardiomyocytes. Cyclosporine A, a CaN inhibitor, markedly suppressed MEF2c nuclear translocation and inhibited TG-induced hypertrophy. These results demonstrate that ERS induces cardiac hypertrophy and that the CaN-MEF2c pathway is involved in ERS-induced hypertrophy in cardiomyocytes.

Eicosapentaenoic acid prevents endothelin-1-induced cardiomyocyte hypertrophy in vitro through the suppression of TGF-β1 and phosphorylated JNK

2006 ◽  
Vol 291 (2) ◽  
pp. H835-H845 ◽  
Author(s):  
Nobutake Shimojo ◽  
Subrina Jesmin ◽  
Sohel Zaedi ◽  
Seiji Maeda ◽  
Masaaki Soma ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cardiac Hypertrophy ◽  
Eicosapentaenoic Acid ◽  
Fish Oil ◽  
Surface Area ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Tgf Β1

The cardiovascular benefit of fish oil in humans and experimental animals has been reported. Endothelin (ET)-1 is a well-known cardiac hypertrophic factor. However, although many studies link a fish oil extract, eicosapentaenoic acid (EPA), to cardiac protection, the effects of EPA on cardiac hypertrophy and underlying mechanism(s) are unclear. The present study investigated whether EPA prevents ET-1-induced cardiomyocyte hypertrophy; the potential pathways likely to underlie such an effect were also investigated. Cardiomyocytes were isolated from neonatal rat heart, cultured for 3 days, and then treated for 24 h with vehicle only (control), treated with 0.1 nM ET-1 only, or pretreated with 10 μM EPA and then treated with 0.1 nM ET-1. The cells were harvested, and changes in cell surface area, protein synthesis, expression of a cytoskeletal (α-actinin) protein, and cell signaling were analyzed. ET-1 induced a 97% increase in cardiomyocyte surface area, a 72% increase in protein synthesis rate, and an increase in expression of α-actinin and signaling molecule [transforming growth factor-β1 (TGF-β1), c-Jun NH2-terminal kinase (JNK), and c-Jun]. Development of these ET-1-induced cellular changes was attenuated by EPA. Moreover, the hypertrophied cardiomyocytes showed a 1.5- and a 1.7-fold increase in mRNA expression of atrial and brain natriuretic peptides, the classical molecular markers of cardiac hypertrophy, respectively; these changes were also suppressed by EPA. Here we show that ET-1 induces cardiomyocyte hypertrophy and expression of hypertrophic markers, possibly mediated by JNK and TGF-β1 signaling pathways. These ET-1-induced effects were blocked by EPA, a major fish oil ingredient, suggesting that fish oil may have beneficial protective effects on cardiac hypertrophy.

scholarly journals JMJD1A Represses the Development of Cardiomyocyte Hypertrophy by Regulating the Expression of Catalase

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Rongjia Zang ◽  
Qingyun Tan ◽  
Fanrong Zeng ◽  
Dongwei Wang ◽  
Shuang Yu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Mechanism Study ◽  
Aortic Constriction ◽  
Rat Cardiomyocytes ◽  
Protein Levels

The histone demethylase JMJD family is involved in various physiological and pathological functions. However, the roles of JMJD1A in the cardiovascular system remain unknown. Here, we studied the function of JMJD1A in cardiac hypertrophy. The mRNA and protein levels of JMJD1A were significantly downregulated in the hearts of human patients with hypertrophic cardiomyopathy and the hearts of C57BL/6 mice underwent cardiac hypertrophy induced by transverse aortic constriction (TAC) surgery or isoproterenol (ISO) infusion. In neonatal rat cardiomyocytes (NRCMs), siRNA-mediated JMJD1A knockdown facilitated ISO or angiotensin II-induced increase in cardiomyocyte size, protein synthesis, and expression of hypertrophic fetal genes, including atrial natriuretic peptide (Anp), brain natriuretic peptide (Bnp), and Myh7. By contrast, overexpression of JMJD1A with adenovirus repressed the development of ISO-induced cardiomyocyte hypertrophy. We observed that JMJD1A reduced the production of total cellular and mitochondrial levels of reactive oxygen species (ROS), which was critically involved in the effects of JMJD1A because either N-acetylcysteine or MitoTEMPO treatment blocked the effects of JMJD1A deficiency on cardiomyocyte hypertrophy. Mechanism study demonstrated that JMJD1A promoted the expression and activity of Catalase under basal condition or oxidative stress. siRNA-mediated loss of Catalase blocked the protection of JMJD1A overexpression against ISO-induced cardiomyocyte hypertrophy. These findings demonstrated that JMJD1A loss promoted cardiomyocyte hypertrophy in a Catalase and ROS-dependent manner.

scholarly journals Qiliqiangxin Attenuates Phenylephrine-Induced Cardiac Hypertrophy through Downregulation of MiR-199a-5p

2016 ◽  
Vol 38 (5) ◽  
pp. 1743-1751 ◽  
Author(s):  
Haifeng Zhang ◽  
Shanshan Li ◽  
Qiulian Zhou ◽  
Qi Sun ◽  
Shutong Shen ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Neonatal Rat ◽  
Immunofluorescent Staining ◽  
Mouse Heart ◽  
Mrna Levels ◽  
Elevated Protein ◽  
Ischemic Stress

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has long been used to treat chronic heart failure. Previous studies demonstrated that QL could prevent cardiac remodeling and hypertrophy in response to hypertensive or ischemic stress. However, little is known about whether QL could modulate cardiac hypertrophy in vitro, and (if so) whether it is through modulation of specific hypertrophy-related microRNA. Methods: The primary neonatal rat ventricular cardiomyocytes were isolated, cultured, and treated with phenylephrine (PE, 50 µmol/L, 48 h) to induce hypertrophy in vitro, in the presence or absence of pretreatment with QL (0.5 µg/ml, 48 h). The cell surface area was determined by immunofluorescent staining for α-actinin. The mRNA levels of hypertrophic markers including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (MYH7) were assayed by qRT-PCRs. The protein synthesis of cardiomyocytes was determined by the protein/DNA ratio. The miR-199a-5p expression level was quantified in PE-treated cardiomyocytes and heart samples from acute myocardial infarction (AMI) mouse model. MiR-199a-5p overexpression was used to determine its role in the anti-hypertrophic effect of QL on cardiomyocytes. Results: PE induced obvious enlargement of cell surface in cardiomyocytes, paralleling with increased ANP, BNP, and MYH7 mRNA levels and elevated protein/DNA ratio. All these changes were reversed by the treatment with QL. Meanwhile, miR-199a-5p was increased in AMI mouse heart tissues. Of note, the increase of miR-199a-5p in PE-treated cardiomyocytes was reversed by the treatment with QL. Moreover, overexpression of miR-199a-5p abolished the anti-hypertrophic effect of QL on cardiomyocytes. Conclusion: QL prevents PE-induced cardiac hypertrophy. MiR-199a-5p is increased in cardiac hypertrophy, while reduced by treatment with QL. miR-199a-5p suppression is essential for the anti-hypertrophic effect of QL on cardiomyocytes.

Abstract 214: MicroRNA-451 Aggravates Lipotoxic Cardiomyopathy Through Suppression of the LKB1/AMPK Signaling Pathway

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Yasuhide Kuwabara ◽  
Takahiro Horie ◽  
Osamu Baba ◽  
Toru Kita ◽  
Takeshi Kimura ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Diabetic Cardiomyopathy ◽  
Calcium Binding ◽  
Saturated Fatty Acids ◽  
Mammalian Target Of Rapamycin ◽  
Neonatal Rat ◽  
Albumin Concentration ◽  
Dependent Manner ◽  
Ceramide Level

Rationale: In some type 2 diabetes mellitus (T2D) patients without hypertension, cardiac hypertrophy and attenuated cardiac function are observed, and this insult is termed “diabetic cardiomyopathy.” Tons of evidence suggests that microRNAs are involved in cardiac diseases. However, the functions of microRNAs in the diabetic cardiomyopathy induced by T2D and obesity are not fully understood. Methods and Results: C57BL/6 mice were fed a high-fat diet (HFD) for 20 weeks, which induced obesity and T2D. MicroRNA microarray and real-time PCR revealed that miR-451 levels were significantly increased in the T2D mouse hearts (n=4-5, p<0.05). Because excess supply of saturated fatty acids is a cause of diabetic cardiomyopathy, we stimulated neonatal rat cardiac myocytes (NRCMs) with palmitate in physiological albumin concentration and confirmed that miR-451 expression was increased in a dose-dependent manner (n=6-12, p<0.01). Loss of miR-451 function ameliorated palmitate-induced lipotoxicity in NRCMs (n=4, p<0.05). Calcium-binding protein 39 (Cab39) is a scaffold protein of liver kinase B1 (LKB1), an upstream kinase of AMP-activated protein kinase (AMPK). Cab39 was a direct target of miR-451 in NRCMs and Cab39 overexpression rescued the palmitate-induced lipotoxicity in NRCMs (n=4, p<0.01). To clarify miR-451 functions in vivo, we generated cardiomyocyte-specific miR-451 knockout (cKO) mice. HFD-induced cardiac hypertrophy and contractile reserves were ameliorated in cKO mice compared with HFD-fed control mice. Protein levels of Cab39 and phosphorylated AMPK were increased and phosphorylated mammalian target of rapamycin (mTOR) was reduced in HFD-fed cKO mouse hearts compared with HFD-fed control mouse hearts (n=10-12, p<0.05). We also measured the lipotoxic intermediates, triglyceride and ceramide, in these mouse hearts using HPLC-evaporative light scattering detector (ELSD). Although there was no difference in triglyceride levels (n=3-5), ceramide level was decreased in HFD-fed cKO mice compared with HFD-fed control mice (n=3-5, p<0.05). Conclusions: Our results indicate that miR-451 exacerbates diabetic cardiomyopathy. miR-451 is a potential therapeutic target for cardiac disease caused by T2D and obesity.

Abstract 2423: B-type Natriuretic Peptide Upregulates Erythropoietin Receptor Gene Expression via Protein Kinase G in Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yoshiaki Ohyama ◽  
Toru Tanaka ◽  
Takehisa Shimizu ◽  
Hiroshi Doi ◽  
Norimichi Koitabashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Protein Kinase ◽  
Cardiac Myocytes ◽  
Natriuretic Peptide ◽  
Neonatal Rat ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Failing Heart ◽  
Epor Expression

Backgroud: Recent studies demonstrated non-hematopoietical effects of Erythropoietin (Epo) and its receptor (EpoR) in a variety of tissues including cardiovascular system. Epo treatment improves cardiac function in patients with heart failure and reduces infarct size after ischemia/reperfusion injury in the heart. However, little attention has been paid for the endogenous regulatory mechanisms regulating EpoR expression. In this study, we hypothesize that B-type natriuretic peptide upregulates EpoR gene expression in failing heart. Methods and Results: Wister rats underwent transverse aortic constriction surgery to induce hypertrophy. RT-PCR analyses of those rats showed that EpoR mRNA levels were increased in the left ventricle and positively correlated with the levels of BNP mRNA (n=10, r=0.67, p<0.05). Next we examined the expression of EpoR in human failing heart by using autopsy specimens and found that EpoR mRNA levels were significantly elevated in patients with dilated cardiomyopathy compared with those in normal heart. Immunohistochemistry of endomyocardial biopsy specimens of failing heart (n=54) showed that EpoR mRNA levels were correlated with severity of cardiac dysfunction estimated by diameter of cardiac chambers, pathomorphology, serum BNP concentration and functional class of New York Heart Association. Interestingly, stimulation of cultured neonatal rat cardiac myocytes with BNP, but not with hypertrophic reagents including endothelin I, angiotensin II and norepinephrine, significantly increased the EpoR mRNA levels in a time-dependent manner. Overexpression of cGMP-dependent protein kinase (PKG) increased EpoR transcript in cultured cardiac myocytes. BNP-induced EpoR expression was abrogated in the presence of KT5823, a specific inhibitor for PKG. Conclusion: These results suggest a role for BNP in mediating an induction of EpoR expression in failing myocardium and indicate that the cardiac EpoR gene is a target of cGMP/PKG signaling.

Abstract 3660: Cardioprotective Effect of Eicosapentaenoic Acid, an Important Fish Oil, through Suppression of Endothelin-1-induced Cardiomyocyte Hypertrophy via PPAR-α

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nobutake Shimojo ◽  
Subrina Jesmin ◽  
Masaaki Soma ◽  
Seiji Maeda ◽  
Takashi Miyauchi ◽  
...  
Keyword(s):  
Eicosapentaenoic Acid ◽  
Fish Oil ◽  
Fold Increase ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Pre Treatment ◽  
Cardiovascular Benefit ◽  
Hypertrophic Changes

A growing body of evidences report the cardiovascular benefit of fish oil including eicosapentaenoic acid (EPA) in humans and experimental animals. While many studies link EPA to cardiac protection, the effect of EPA on endothelin (ET)-1-induced cardiomyocyte hypertrophy is unknown. On the other hand, the previous study demonstrated peroxisomal proliferator-activated receptor (PPAR) -α ligand (fenofibrate) prevents ET-1-induced cardiomyocyte hypertrophy. Though EPA is one of the lignads of PPAR-α, there was no study linking relationship between EPA and PPAR-α on hypertrophied cadiomyocyte. The present study investigated whether ET-1-induced cardiomyocyte hypertrophy could be prevented by the pre-treatment of EPA. Cardiomyocytes were accumulated from neonatal rat heart, cultured and at day 4 of culture, the cardiomyocytes were divided into three groups: control, ET-1 (0.1nM) treated and EPA-pre-treated (10μM) ET-1 groups. A 90% increase in cardiomyocyte surface area, a 75% increase in protein synthesis rate and an elevated actinin expression in cardiomyocyte were observed after ET-1 administration and these changes were greatly prevented by EPA pre-treatment. ET-1-induced hypertrophied cardiomyocytes showed a 2.3-fold and 2.1-fold increase in ANP and BNP mRNA expression, respectively, which were also suppressed by EPA pre-treatment. Pre-treatment of EPA could also attenuate phosphorylated JNK (an important component of MAPK cascade), c-Jun and PPAR-α in ET-1-induced hypertrophied cardiomyocytes. In conclusion, the present study showed that ET-1 can induce significant hypertrophic changes in cardiomyocytes with upregulation of important hypertrophic markers, and that this remodeling was effectively prevented by the pre-administration of EPA through suppressing PPAR-α, phosporylated JNK, and c-Jun.

Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy

2006 ◽  
Vol 26 (3) ◽  
pp. 180-191 ◽  
Author(s):  
Shawn D. Hingtgen ◽  
Xin Tian ◽  
Jusan Yang ◽  
Shannon M. Dunlay ◽  
Andrew S. Peek ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Dominant Negative ◽  
Time Dependent ◽  
Neonatal Rat ◽  
Signaling Cascade ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Akt Activation

Angiotensin II (ANG II) has profound effects on the development and progression of pathological cardiac hypertrophy; however, the intracellular signaling mechanisms are not fully understood. In this study, we used genetic tools to test the hypothesis that increased formation of superoxide (O2−·) radicals from a Rac1-regulated Nox2-containing NADPH oxidase is a key upstream mediator of ANG II-induced activation of serine-threonine kinase Akt, and that this signaling cascade plays a crucial role in ANG II-dependent cardiomyocyte hypertrophy. ANG II caused a significant time-dependent increase in Rac1 activation and O2−· production in primary neonatal rat cardiomyocytes, and these responses were abolished by adenoviral (Ad)-mediated expression of a dominant-negative Rac1 (AdN17Rac1) or cytoplasmic Cu/ZnSOD (AdCu/ZnSOD). Moreover, both AdN17Rac1 and AdCu/ZnSOD significantly attenuated ANG II-stimulated increases in cardiomyocyte size. Quantitative real-time PCR analysis demonstrated that Nox2 is the homolog expressed at highest levels in primary neonatal cardiomyocytes, and small interference RNA (siRNA) directed against it selectively decreased Nox2 expression by >95% and abolished both ANG II-induced O2−· generation and cardiomyocyte hypertrophy. Finally, ANG II caused a time-dependent increase in Akt activity via activation of AT1 receptors, and this response was abolished by Ad-mediated expression of cytosolic human O2−· dismutase (AdCu/ZnSOD). Furthermore, pretreatment of cardiomyocytes with dominant-negative Akt (AdDNAkt) abolished ANG II-induced cellular hypertrophy. These findings suggest that O2−· generated by a Nox2-containing NADPH oxidase is a central mediator of ANG II-induced Akt activation and cardiomyocyte hypertrophy, and that dysregulation of this signaling cascade may play an important role in cardiac hypertrophy.

scholarly journals Sophoricoside ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Maomao Gao ◽  
Fengjiao Hu ◽  
Manli Hu ◽  
Yufeng Hu ◽  
Hongjie Shi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Protective Effects ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy ◽  
Compound C

Abstract Aim: The study aims to evaluate protective effects of sophoricoside (Sop) on cardiac hypertrophy. Meanwhile, the potential and significance of Sop should be broadened and it should be considered as an attractive drug for the treatment of pathological cardiac hypertrophy and heart failure. Methods: Using the phenylephrine (PE)-induced neonatal rat cardiomyocytes (NRCMs) enlargement model, the potent protection of Sop against cardiomyocytes enlargement was evaluated. The function of Sop was validated in mice received transverse aortic coarctation (TAC) or sham surgery. At 1 week after TAC surgery, mice were treated with Sop for the following 4 weeks, the hearts were harvested after echocardiography examination. Results: Our study revealed that Sop significantly mitigated TAC-induced heart dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, Sop treatment induced a remarkable activation of AMPK/mTORC1-autophagy cascade following sustained hypertrophic stimulation. Importantly, the protective effect of Sop was largely abolished by the AMPKα inhibitor Compound C, suggesting an AMPK activation-dependent manner of Sop function on suppressing pathological cardiac hypertrophy. Conclusion: Sop ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy. Hence, Sop might be an attractive candidate for the treatment of pathological cardiac hypertrophy and heart failure.

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