scholarly journals PKCα regulates the hypertrophic growth of cardiomyocytes through extracellular signal–regulated kinase1/2 (ERK1/2)

2002 ◽  
Vol 156 (5) ◽  
pp. 905-919 ◽  
Author(s):  
Julian C. Braz ◽  
Orlando F. Bueno ◽  
Leon J. De Windt ◽  
Jeffery D. Molkentin
Keyword(s):  
Marker Gene ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Leucine Incorporation ◽  
Wild Type ◽  
Rat Cardiomyocytes ◽  
Signal Transducers ◽  
Hypertrophic Growth ◽  
Extracellular Signal

Members of the protein kinase C (PKC) isozyme family are important signal transducers in virtually every mammalian cell type. Within the heart, PKC isozymes are thought to participate in a signaling network that programs developmental and pathological cardiomyocyte hypertrophic growth. To investigate the function of PKC signaling in regulating cardiomyocyte growth, adenoviral-mediated gene transfer of wild-type and dominant negative mutants of PKCα, βII, δ, and ε (only wild-type ζ) was performed in cultured neonatal rat cardiomyocytes. Overexpression of wild-type PKCα, βII, δ, and ε revealed distinct subcellular localizations upon activation suggesting unique functions of each isozyme in cardiomyocytes. Indeed, overexpression of wild-type PKCα, but not βII, δ, ε, or ζ induced hypertrophic growth of cardiomyocytes characterized by increased cell surface area, increased [3H]-leucine incorporation, and increased expression of the hypertrophic marker gene atrial natriuretic factor. In contrast, expression of dominant negative PKCα, βII, δ, and ε revealed a necessary role for PKCα as a mediator of agonist-induced cardiomyocyte hypertrophy, whereas dominant negative PKCε reduced cellular viability. A mechanism whereby PKCα might regulate hypertrophy was suggested by the observations that wild-type PKCα induced extracellular signal–regulated kinase1/2 (ERK1/2), that dominant negative PKCα inhibited PMA-induced ERK1/2 activation, and that dominant negative MEK1 (up-stream of ERK1/2) inhibited wild-type PKCα–induced hypertrophic growth. These results implicate PKCα as a necessary mediator of cardiomyocyte hypertrophic growth, in part, through a ERK1/2-dependent signaling pathway.

scholarly journals The Transcription Factor GATA4 Is Activated by Extracellular Signal-Regulated Kinase 1- and 2-Mediated Phosphorylation of Serine 105 in Cardiomyocytes

2001 ◽  
Vol 21 (21) ◽  
pp. 7460-7469 ◽  
Author(s):  
Qiangrong Liang ◽  
Russell J. Wiese ◽  
Orlando F. Bueno ◽  
Yan-Shan Dai ◽  
Bruce E. Markham ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Phosphorylation Site ◽  
Dominant Negative ◽  
Site Directed Mutagenesis ◽  
Mitogen Activated Protein Kinase ◽  
Cardiomyocyte Hypertrophy ◽  
Hypertrophic Growth ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

ABSTRACT The zinc finger-containing transcription factor GATA4 has been implicated as a critical regulator of multiple cardiac-expressed genes as well as a regulator of inducible gene expression in response to hypertrophic stimulation. Here we demonstrate that GATA4 is itself regulated by the mitogen-activated protein kinase signaling cascade through direct phosphorylation. Site-directed mutagenesis and phospho-specific GATA4 antiserum revealed serine 105 as the primary site involved in agonist-induced phosphorylation of GATA4. Infection of cultured cardiomyocytes with an activated MEK1-expressing adenovirus induced robust phosphorylation of serine 105 in GATA4, while a dominant-negative MEK1-expressing adenovirus blocked agonist-induced phosphorylation of serine 105, implicating extracellular signal-regulated kinase (ERK) as a GATA4 kinase. Indeed, bacterially purified ERK2 protein directly phosphorylated purified GATA4 at serine 105 in vitro. Phosphorylation of serine 105 enhanced the transcriptional potency of GATA4, which was sensitive to U0126 (MEK1 inhibitor) but not SB202190 (p38 inhibitor). Phosphorylation of serine 105 also modestly enhanced the DNA binding activity of bacterially purified GATA4. Finally, induction of cardiomyocyte hypertrophy with an activated MEK1-expressing adenovirus was blocked with a dominant-negative GATA4-engrailed-expressing adenovirus. These results suggest a molecular pathway whereby MEK1-ERK1/2 signaling regulates cardiomyocyte hypertrophic growth through the transcription factor GATA4 by direct phosphorylation of serine 105, which enhances DNA binding and transcriptional activation.

Carbonic anhydrase II promotes cardiomyocyte hypertrophy

2012 ◽  
Vol 90 (12) ◽  
pp. 1599-1610 ◽  
Author(s):  
Brittany F. Brown ◽  
Anita Quon ◽  
Jason R.B. Dyck ◽  
Joseph R. Casey
Keyword(s):  
Carbonic Anhydrase ◽  
Ventricular Myocytes ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Carbonic Anhydrase Ii ◽  
Cardiomyocyte Hypertrophy ◽  
Wild Type ◽  
Over Expression ◽  
Pathological Cardiac Hypertrophy ◽  
Neonatal Rat Ventricular Myocytes

Pathological cardiac hypertrophy, the maladaptive remodelling of the myocardium, often progresses to heart failure. The sodium–proton exchanger (NHE1) and chloride–bicarbonate exchanger (AE3) have been implicated as important in the hypertrophic cascade. Carbonic anhydrase II (CAII) provides substrates for these transporters (protons and bicarbonate, respectively). CAII physically interacts with NHE1 and AE3, enhancing their respective ion transport activities by increasing the concentration of substrate at their transport sites. Earlier studies found that a broad-spectrum carbonic anhydrase inhibitor prevented cardiomyocyte hypertrophy (CH), suggesting that carbonic anhydrase is important in the development of hypertrophy. Here we investigated whether cytosolic CAII was the CA isoform involved in hypertrophy. Neonatal rat ventricular myocytes (NRVMs) were transduced with recombinant adenoviral constructs to over-express wild-type or catalytically inactive CAII (CAII-V143Y). Over-expression of wild-type CAII in NRVMs did not affect CH development. In contrast, CAII-V143Y over-expression suppressed the response to hypertrophic stimuli, suggesting that CAII-V143Y behaves in a dominant negative fashion over endogenous CAII to suppress hypertrophy. We also examined CAII-deficient (Car2) mice, whose hearts exhibit physiological hypertrophy without any decrease in cardiac function. Moreover, cardiomyocytes from Car2 mice do not respond to prohypertrophic stimulation. Together, these findings support a role of CAII in promoting CH.

scholarly journals Adenosine kinase regulation of cardiomyocyte hypertrophy

2011 ◽  
Vol 300 (5) ◽  
pp. H1722-H1732 ◽  
Author(s):  
John T. Fassett ◽  
Xinli Hu ◽  
Xin Xu ◽  
Zhongbing Lu ◽  
Ping Zhang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cell Size ◽  
Adenosine Receptors ◽  
Adenosine Kinase ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Mtorc1 Signaling ◽  
Constitutively Active

There is evidence that extracellular adenosine can attenuate cardiac hypertrophy, but the mechanism by which this occurs is not clear. Here we investigated the role of adenosine receptors and adenosine metabolism in attenuation of cardiomyocyte hypertrophy. Phenylephrine (PE) caused hypertrophy of neonatal rat cardiomyocytes with increases of cell surface area, protein synthesis, and atrial natriuretic peptide (ANP) expression. These responses were attenuated by 5 μM 2-chloroadenosine (CADO; adenosine deaminase resistant adenosine analog) or 10 μM adenosine. While antagonism of adenosine receptors partially blocked the reduction of ANP expression produced by CADO, it did not restore cell size or protein synthesis. In support of a role for intracellular adenosine metabolism in regulating hypertrophy, the adenosine kinase (AK) inhibitors iodotubercidin and ABT-702 completely reversed the attenuation of cell size, protein synthesis, and expression of ANP by CADO or ADO. Examination of PE-induced phosphosignaling pathways revealed that CADO treatment did not reduce AKTSer473 phosphorylation but did attenuate sustained phosphorylation of RafSer338 (24–48 h), mTORSer2448 (24–48 h), p70S6kThr389 (2.5–48 h), and ERKThr202/Tyr204 (48 h). Inhibition of AK restored activation of these enzymes in the presence of CADO. Using dominant negative and constitutively active Raf adenoviruses, we found that Raf activation is necessary and sufficient for PE-induced mTORC1 signaling and cardiomyocyte hypertrophy. CADO treatment still blocked p70S6kThr389 phosphorylation and hypertrophy downstream of constitutively active Raf, however, despite a high level phosphorylation of ERKThr202/Tyr204 and AKTSer473. Reduction of Raf-induced p70S6kThr389 phosphorylation and hypertrophy by CADO was reversed by inhibiting AK. Together, these results identify AK as an important mediator of adenosine attenuation of cardiomyocyte hypertrophy, which acts, at least in part, through inhibition of Raf signaling to mTOR/p70S6k.

PKC-ε regulation of extracellular signal-regulated kinase: a potential role in phenylephrine-induced cardiocyte growth

2004 ◽  
Vol 286 (6) ◽  
pp. H2195-H2203 ◽  
Author(s):  
Vijay U. Rao ◽  
Hirokazu Shiraishi ◽  
Paul J. McDermott
Keyword(s):  
Growth Regulation ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Neonatal Rat ◽  
Inhibitory Effects ◽  
Hypertrophic Growth ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Acute Increase

Hypertrophic growth of cardiac muscle is dependent on activation of the PKC-ε isoform. To define the effectors of PKC-ε involved in growth regulation, recombinant adenoviruses were used to overexpress either wild-type PKC-ε (PKC-ε/WT) or dominant negative PKC-ε (PKC-ε/DN) in neonatal rat cardiocytes. PKC-ε/DN inhibited acute activation of PKC-ε produced in response to phorbol ester and reduced ERK1/2 activity as measured by the phosphorylation of p42 and p44 isoforms. The inhibitory effects were specific to PKC-ε because PKC-ε/DN did not prevent translocation of either PKC-α or PKC-δ. Overexpression of PKC-ε/DN blunted the acute increase in ERK1/2 phorphorylation induced by the α1-adrenergic agonist phenylephrine (PE ). Inhibition of PKC-δ with rottlerin potentiated the effects of PE on ERK1/2 phosphorylation. PKC-ε/DN adenovirus also blocked cardiocyte growth as measured after 48 h of PE treatment, although the multiplicity of infection was lower than that required to block acute ERK1/2 activation. PE activated p38 mitogen-activated protein kinase as measured by its phosphorylation, but the response was not blocked by PKC inhibitors or by overexpression of PKC-ε/DN. Taken together, these studies show that the hypertrophic agonist PE regulates ERK1/2 activity in cardiocytes by a pathway dependent on PKC-ε and that PE-induced growth is mediated by PKC-ε.

Abstract P320: The Gut Microbial Metabolite Butyrate Suppresses Cardiac Hypertrophy Via An Epigenetic Mechanism

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Masahiko Umei ◽  
Hiroshi Akazawa ◽  
Akiko Saga-Kamo ◽  
Hiroki Yagi ◽  
Qing Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
Short Chain Fatty Acid ◽  
Chain Fatty Acid ◽  
Epigenetic Mechanism ◽  
Neonatal Rat ◽  
Short Chain ◽  
Rat Cardiomyocytes ◽  
Hypertrophic Growth

Introduction: Short-chain fatty acids (SCFA) are one of the gut microbial metabolites that can influence host health and disease. We previously reported that gut dysbiosis is associated with heart failure, and that the proportion of butyrate-producing bacteria is decreased in the gut of patients with heart failure. Purpose: We investigated the molecular mechanism of butyrate in the development of cardiac hypertrophy. Methods and Results: Single-cell transcriptome analysis and co-expression network analysis revealed that G protein-coupled receptors for short-chain fatty acid receptors were not expressed in cardiomyocytes and that Olfr78 was expressed in vascular smooth muscle cells in the heart. On the other hand, treatment with butyrate inhibited ET1-induced and isoproterenol (ISO)-induced hypertrophic growth in cultured neonatal rat cardiomyocytes. Moreover, butyrate increased the acetylation levels of histone H3, suggesting the inhibitory effect of butyrate on HDAC. In addition, butyrate caused the degradation of HDAC2 and up-regulation of Inpp5f, encoding inositol polyphosphate-5-phosphatase f, leading to a significant decrease in the phosphorylation levels of Akt and glycogen synthase kinase 3β (GSK3β). Finally, intraperitoneal injection of butyrate inhibited ISO-induced cardiac hypertrophy in mice. These results suggest that butyrate protects against hypertrophic responses via suppression of the Akt-GSK3β pathway through HDAC inhibition. Conclusion: In the heart, there were no known short-chain fatty acid receptors in cardiomyocytes. However, butyrate was shown to have an epigenetic mechanism in suppressing effect on cardiomyocyte hypertrophy via suppression of HDAC2-Akt-GSK3β axis. Our results uncover a potential link between dysbiosis of intestinal microbiota and the development of cardiac hypertrophy.

Abstract 934: Contributory Role of VEGF Overexpression in Endothelin-1-induced Cardiomyocyte Hypertrophy: Involvement of Hyopoxia Inducible Factor

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nobutake Shimojo ◽  
Subrina Jesmin ◽  
Yuichi Hattori ◽  
Seiji Maeda ◽  
Takashi Miyauchi ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Hypoxia Inducible Factor ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Rat Cardiomyocytes ◽  
Endothelin 1 ◽  
Vegf Signaling ◽  
Endothelial Growth Factor

Although endothelin-1 (ET-1) stimulates vascular endothelial growth factor (VEGF) expression in a variety of cells, including endothelial cells and vascular smooth muscle cells, the effect of ET-1 on expression of VEGF and its receptors in cardiomyocytes is unknown. In the present study, we found that treatment of neonatal rat cardiomyocytes with ET-1 for 24 h resulted in upregulation of VEGF and its two principle receptors, fetal liver kinase (flk)-1 and fms-like tyrosine kinase (flt)-1, in a concentration-dependent manner (10 −12 -10 −6 M). ET-1 treatment also caused significant cardiomyocyte hypertrophy, as indicated by increases in cell surface area (2.0-fold compared to control) and 14 C-leucine uptake (1.8 fold) by cardiomyocytes. And this ET-1 mediated upregulation of VEGF in cardiomyocytes was associated with the induction of hypoxia inducible factor (HIF)-1β and HIF-2α, not HIF-1α. Treatment with TA-0201 (10 −6 M), an ET A selective blocker, eliminated ET-1-induced overexpression of VEGF and its receptors as well as cardiomyocyte hypertrophy. Treatment with VEGF neutralizing peptides (5–10 μg/ml) partially but significantly inhibited ET-1-induced cardiomyocyte hypertrophy. Both TA-0201 and VEGF neutralizing peptides also significantly prevented the increase of phosphorylated KDR, which implies the activation of VEGF system in ET-1 induced hypertrophied cardiomyocyte. These results suggest that ET-1 treatment of cardiomyocytes promotes overexpression of VEGF and its receptors via activation of ET A receptors, and consequently the upregulated VEGF signaling system appears to contribute, at least in part, to ET-1-induced cardiomyocyte hypertrophy.

Abstract 182: CTRP9 - A Novel Cardiac Derived Secreted Factor With Anti-hypertrophic Properties

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Astrid H Breitbart ◽  
Florian Brandes ◽  
Oliver Müller ◽  
Natali Froese ◽  
Mortimer Korf-Klingebiel ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Real Time ◽  
Real Time Pcr ◽  
Weight Ratio ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Quantitative Real Time Pcr ◽  
Rat Cardiomyocytes ◽  
Knock Out

Background: CTRP9 (also called C1qtnf9) is a newly discovered secreted protein and a paralog of adiponectin. The biological functions of CTRP9, however, are still largely unknown. Results: Although previous data from a semi-quantitative real-time PCR had suggested that CTRP9 is mainly secreted by adipose tissue, we found its mRNA to be predominantly expressed in the heart by quantitative real-time PCR. Interestingly, we identified CTRP9 mRNA as significantly upregulated in hypertrophied mouse hearts (after 2 weeks of aortic constriction, TAC) as well as in hypertrophied human hearts (24±4-fold versus healthy human myocardium; p<0.01). LacZ staining in myocardial sections of C1qtnf9 tm1(KOMP)Vlcg mice (knock-out for CTRP9, containing a lacZ cassette to replace exon 1-3 of the gene) revealed exclusive expression of CTRP9 in capillary and venous endothelial cells. Adenoviral overexpression of CTRP9 or recombinant CTRP9 strongly inhibited cardiomyocyte hypertrophy (assessed as cell size, protein/DNA-ratio, expression of skeletal α-actin) after stimulation with phenylephrine (PE). Accordingly, myocardial overexpression of CTRP9 via a cardioselective adeno-associated virus (AAV9-CTRP9) in mice dramatically reduced cardiac hypertrophy after two weeks of pressure overload (heart weight/body weight ratio, HW/BW in mg/g: AAV9-control 6.5±0.2 versus AAV9-CTRP9 5.6±0.2; p<0.01). In turn, downregulation of CTRP9 by a specific siRNA aggravated cardiomyocyte growth in response to PE in vitro and CTRP9 knock-out (KO) mice exerted an enhanced hypertrophic response after two weeks of TAC in vivo (% increase in HW/BW versus sham: wild-type 77±13, KO 106±9; p<0.05). Mechanistically, we found that CTRP9 binds to the adiponectin receptor 1 (AdipoR1) and inhibits prohypertrophic mTOR signalling in cardiac myocytes. SiRNA mediated downregulation of AdipoR1 or mTOR in neonatal rat cardiomyocytes abolished the anti-hypertrophic effect of CTRP9. Conclusion: Endothelial cell derived CTRP9 inhibits cardiac hypertrophy through binding to AdipoR1 and inhibition of the mTOR pathway in cardiomyocytes. Therefore, myocardial application of CTRP9 could be a novel strategy to combat pathological cardiac hypertrophy.

Abstract 855: Circulating Mesoangioblasts Differentiate Into Cardiac Myocytes And Improve Function After Acute Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Masayoshi Iwasaki ◽  
Masamichi Koyanagi ◽  
Stefan Rapp ◽  
Corina Schuetz ◽  
Philipp Bushoven ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Troponin T ◽  
Marker Gene ◽  
Left Ventricular ◽  
Cardiac Differentiation ◽  
Neonatal Rat ◽  
Stem Cell Markers ◽  
Rt Pcr ◽  
Rat Cardiomyocytes

Mesoangioblasts (MAB) are vessel-associated cells identified during embryonic development. In contrast to hemangioblasts, MAB express mesenchymal (CD73) and endothelial marker, but lack the hematopoietic marker CD45. We recently identified circulating MAB in children. Children-derived MAB showed vigorous proliferation capacity and high telomerase activity. However, the potential of cardiac differentiation in these cells was not elucidated. Therefore, we tested the capacity of children-derived MAB to aquire a cardiomyogenic phenotype. MAB expressed several cardiac transcription factors such as Nkx2.5, GATA4 and MEF2C and the stem cell markers c-kit and islet-1. In order to assess cardiac differentiation capacity, we performed co-culture assays with neonatal rat cardiomyocytes (CM). Immunochemical analysis revealed that MAB expressed cardiac α-sarcomeric actinin 6 days after co-culture. Moreover, human troponin T (TnT) was expressed as demonstrated by human specific RT-PCR. To confirm these data, we examined TnT expression in MAB isolated of a 2 years old patient with a known mutation of TnT. Sequences of the cloned RT-PCR products were identical to human TnT except for the known mutation providing genetic proof of concept for cardiac differentiation. In order to exclude fusion between MAB and CM as a mechanism, we used paraformaldehyde-fixed CM as scaffold. In this assay, human TnT also was detected, indicating that differentiation is sufficient to induce cardiac marker gene expression. Next, we tested the effect of MAB to improve cardiac function. MAB were injected intramuscularly in nude mice after myocardial infarction. Functional analysis using Millar catheter 2 weeks after infarction demonstrated that cell therapy lowered filling pressure and preserved diastolic function when compared to the PBS injected group (LVEDP: −20.3%, tau: −20.6%, vs PBS injected heart). Furthermore, left ventricular volume was also decreased (LVEDV/weight −27.3%). In summary, children-derived MAB express cardiac-specific genes after co-culture with CM and improved cardiac function in vivo. Given that MAB can be easily isolated and expanded from peripheral blood, these cells might be suitable to augment cardiac repair in children with heart failure.

Abstract 15445: The Sirtuin SIRT3 Blocks Doxorubicin-induced Cardiac Hypertrophic Response of Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Vinodkumar Pillai ◽  
Sadhana Samant ◽  
Nagalingam Sundaresan ◽  
Gene Kim ◽  
Mahesh P Gupta
Keyword(s):  
Negative Regulator ◽  
Neonatal Rat ◽  
Whole Body ◽  
Wild Type ◽  
Electron Microscopic ◽  
Specific Expression ◽  
Rat Cardiomyocytes ◽  
Fluorescent Intensity ◽  
Hypertrophic Response

Background and objective: Doxorubicin is a chemotherapeutic drug widely used to treat variety of cancers. One of the serious side effects of doxorubicin is its toxicity to the heart. Previously, we have shown that overexpression of SIRT3 blocks the hypertrophic response of the heart to agonist treatments. This study was undertaken to investigate whether SIRT3 can also attenuate the doxorubicin-induced cardiac hypertrophic response in mice. Methods and results: Neonatal rat cardiomyocytes overexpressed with SIRT3 and treated with doxorubicin (10μM) showed 28% reduced mean fluorescent intensity for CM-H 2 DCFDA dye, compared to mock infected control cells treated with doxorubicin, thus suggesting that SIRT3 was capable of blocking doxorubicin-induced ROS synthesis in cardiomyocytes. To examine the cardioprotective effects of SIRT3 in doxorubicin-induced cardiotoxicity in vivo ; we used a cumulative dose of 15mg/kg of doxorubicin for two different time points. One group of mice was treated intraperitoneally with 5mg/kg doxorubicin or an equal volume of saline every two weeks for a total of three doses. Transgenic mice having cardiac specific expression of SIRT3 (SIRT3-Tg) showed 33% reduced HW/BW ratio compared to control mice. Echocardiographic evaluation of hearts showed significantly reduced fractional shortening in control mice, compared to SIRT3-Tg mice (24.6 vs 34.7 %, P<0.05). SIRT3-Tg mice also showed significantly reduced fetal gene expression for ANF, βMHC and collagen-1 as determined by RT-PCR. Masson’s trichrome staining showed significantly reduced fibrosis in doxorubicin treated SIRT3-Tg mice compared to its control. Furthermore, electron microscopic analysis showed preserved mitochondrial and sarcomeres structures in doxorubicin treated SIRT3-Tg hearts, whereas in wild-type hearts these structures were highly disorganized. Second group of mice that received 15mg/kg dose for two weeks also showed similar results. Contrary to this, whole body SIRT3 knockout mice showed exacerbated cardiac hypertrophic response compared to wild-type mice in response to doxorubicin treatment. Conclusion: These results demonstrated that SIRT3 is an endogenous negative regulator of doxorubicin-induced cardiac hypertrophic response.

Abstract 14951: Maresin 1 Induces Cardiomyocyte Hypertrophy Through RORα/IGF-1/PI3K/Akt Pathway

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tri Wahyuni ◽  
Arisa Kobayashi ◽  
Shota Tanaka ◽  
Yoshiaki Miyake ◽  
Ayaha Yamamoto ◽  
...  
Keyword(s):  
Surface Area ◽  
Neonatal Rat ◽  
Immunofluorescent Staining ◽  
Akt Pathway ◽  
Cardiomyocyte Hypertrophy ◽  
Lipid Mediator ◽  
Myocardial Inflammation ◽  
Rat Cardiomyocytes ◽  
Phosphorylated Akt ◽  
Maresin 1

Myocardial inflammation is a critical event for the onset and progression of the heart failure. Maresin 1 (MaR1) was originally identified as a macrophage lipid mediator that exhibits anti-inflammatory and pro-resolving activities. Though it is widely accepted that macrophages positively and negatively regulate myocardial inflammation through cytokines and growth factors, the biological functions of lipid mediators, such as MaR1, in cardiomyocytes remain to be addressed. This study explored the functional roles of MaR1 in cardiomyocytes. Neonatal rat cardiomyocytes (NRCMs) were stimulated with MaR1 for 48 hours. Immunofluorescent staining with anti-sarcomeric α-actinin antibody revealed that MaR1 (50 nM) induced a significant increase in cardiomyocyte surface area (1760.34±66.86μm 2 vs. 960.83±29.46μm 2 ). Quantitative RT-PCR analyses revealed that the treatment with MaR1 upregulated the expression of IGF-1 mRNA (2.9±0.6 folds), accompanied by the enhanced level of total and phosphorylated Akt. Interestingly, MaR1 did not influence the expression of BNP and skeletal actin significantly, suggesting that MaR1 induced physiological hypertrophy. Since MaR1 is a ligand of RORα, we examined the effects of RORα blockade (SR3335) and found that this compound inhibited the increase of cardiomyocyte surface area by abrogating MaR1-mediated activation of IGF-1/PI3K/Akt pathway. Importantly, treatment with wortmannin or NVP-AEW541, inhibitors for PI3K or IGF-1 receptor, respectively, suppressed MaR1-induced cardiomyocyte hypertrophy, indicating that IGF-1/PI3K/Akt pathway is essential for MaR1-induced hypertrophy. In conclusion, MaR1 is a novel lipid mediator that induces physiological cardiomyocyte hypertrophy by activating RORα/IGF-1/PI3K/Akt pathway. Thus, MaR1 could coordinate the resolving process and tissue recovery in myocardial inflammation.

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