scholarly journals Phytosterol supplementation reduces metabolic activity and slows cell growth in cultured rat cardiomyocytes

2011 ◽  
Vol 106 (4) ◽  
pp. 540-548 ◽  
Author(s):  
Francesca Danesi ◽  
Federico Ferioli ◽  
Maria Fiorenza Caboni ◽  
Elisa Boschetti ◽  
Mattia Di Nunzio ◽  
...  
Keyword(s):  
Cell Growth ◽  
Metabolic Activity ◽  
Membrane Integrity ◽  
Cholesterol Content ◽  
Heart Tissue ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Cholesterol Lowering ◽  
Rat Cardiomyocytes ◽  
Slowing Down

Besides being cholesterol-lowering agents, phytosterols (PS) can inhibit the growth and development of tumours. The anti-neoplastic activity is accounted for by PS incorporation into cell membranes, resulting in the interference of membrane functionality. The similarity between the PS cholesterol-lowering and anti-neoplastic effective doses deserves attention on the possible adverse effects even in non-neoplastic cells. To date, few studies have addressed the clarification of this important issue. In the present study, we supplemented primary, non-neoplastic neonatal rat cardiomyocytes with two different PS concentrations (3 or 6 μg/ml), both within the range of human plasma concentration. Cardiac cells were chosen as an experimental model since the heart has been reported as the target organ for subchronic toxicity of PS. Following supplementation, a dose-dependent incorporation of PS and a decrease in cholesterol content were clearly evidenced. PS did not induce apoptosis but caused a reduction in metabolic activity (measured as 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) conversion) and a slowing down of cell growth. The lower MTT conversion and the similar lactate dehydrogenase release could suggest that PS more efficiently target mitochondria than plasma membrane integrity. The replacement of cholesterol by PS could also have caused the observed slowing down of cell growth and the reduction in metabolic activity, which could rely on the PS increase, cholesterol decrease, or both. The present study is the first report on the effect of PS in cardiac cells, and although it is difficult to translate the obtained results to the health of heart tissue, it raises concerns about the safety of long-term exposure to physiologically relevant PS concentrations.

scholarly journals Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1309
Author(s):  
Sandra Funcke ◽  
Tessa R. Werner ◽  
Marc Hein ◽  
Bärbel M. Ulmer ◽  
Arne Hansen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Ischemia Reperfusion ◽  
Heart Tissue ◽  
Contractile Force ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Engineered Heart Tissue ◽  
Hypoxia Reoxygenation

Intermittent hypoxia and various pharmacological compounds protect the heart from ischemia reperfusion injury in experimental approaches, but the translation into clinical trials has largely failed. One reason may lie in species differences and the lack of suitable human in vitro models to test for ischemia/reperfusion. We aimed to develop a novel hypoxia-reoxygenation model based on three-dimensional, spontaneously beating and work performing engineered heart tissue (EHT) from rat and human cardiomyocytes. Contractile force, the most important cardiac performance parameter, served as an integrated outcome measure. EHTs from neonatal rat cardiomyocytes were subjected to 90 min of hypoxia which led to cardiomyocyte apoptosis as revealed by caspase 3-staining, increased troponin I release (time control vs. 24 h after hypoxia: cTnI 2.7 vs. 6.3 ng/mL, ** p = 0.002) and decreased contractile force (64 ± 6% of baseline) in the long-term follow-up. The detrimental effects were attenuated by preceding the long-term hypoxia with three cycles of 10 min hypoxia (i.e., hypoxic preconditioning). Similarly, [d-Ala2, d-Leu5]-enkephalin (DADLE) reduced the effect of hypoxia on force (recovery to 78 ± 5% of baseline with DADLE preconditioning vs. 57 ± 5% without, p = 0.012), apoptosis and cardiomyocyte stress. Human EHTs presented a comparable hypoxia-induced reduction in force (55 ± 5% of baseline), but DADLE failed to precondition them, likely due to the absence of δ-opioid receptors. In summary, this hypoxia-reoxygenation in vitro model displays cellular damage and the decline of contractile function after hypoxia allows the investigation of preconditioning strategies and will therefore help us to understand the discrepancy between successful conditioning in vitro experiments and its failure in clinical trials.

Abstract 1471: Development and Characterization of Force Generating Human Engineered Heart Tissue from Embryonic Stem Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Christina Rogge ◽  
Michael Didié ◽  
Erich Wettwer ◽  
Ursula Ravens ◽  
Ralph Graichen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Heart Tissue ◽  
Cardiac Repair ◽  
Embryoid Bodies ◽  
Laser Scanning Microscopy ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Engineered Heart Tissue

Engineered Heart Tissue (EHT) from neonatal rat cardiomyocytes has been used successfully as in vitro model and in cardiac repair. Here, we hypothesized that human embryonic stem cells (hESC) can be used to generate EHT with properties of native myocardium. Methods: hESC (hES3-ENVY) were differentiated in embryoid bodies, enzymatically dispersed, and subjected to EHT-generation in circular casting molds (1.5x10 6 cells, 0.4 mg collagen, 10% Matrigel/EHT; inner/outer diameter - 2/4 mm). Contractile function was assessed 10 days after casting under isometric conditions (37°C, 1.5 Hz, Tyrode’s solution). Action potentials (AP) were recorded in spontaneously contracting EHTs with intracellular electrodes (37°C, Tyrode’s solution). Calcium gradients were assessed by confocal laser scanning microscopy (CLSM) after rhod-2 loading. EHT-morphology was examined by CLSM and electron microscopy (EM). Results: hESC-EHTs contracted synchronously and spontaneously at 1.1±0.1 Hz (n=3). Increasing concentrations of extracellular calcium (0.2–2.4 mM) enhanced force of contraction from 53±8 to 199±22 μN (n=8, p<0.05; EC 50 : 0.8±0.04 mM). Isoprenaline (1 μM) at 0.4 mM calcium increased twitch tension from 61±7 to 108±15 μN (n=8, p<0.05) and shortened relaxation time from 111±6 to 87±4 ms (n=3, p<0.05). Cardiomyocytes within EHTs formed a functional syncytium composed of predominantly oriented muscle strands with a high degree of sarcomere differentiation (CLSM, EM). Cell-cell contacts through adherens junctions were identified by EM. Synchronous calcium gradient spread in spontaneously contracting EHTs indicated electrical coupling of individual cells within the multicellular constructs. AP recordings identified pacemaker cells (spontaneous diastolic depolarization) and cells with a flat phase 4 of the AP (working myocardium-like cells). Pharmacological studies demonstrated the presence and functional relevance of I Na (10–30 μM flecainide), I Ca (1 μM nisoldipine), and I Kr (1–5 μM E4031). Conclusion: Human force-generating EHT with functional and morphological properties of native myocardium can be generated. Ultimately, hESC-EHTs may constitute a model system for substance screening and could further be utilized in cardiac repair.

MicroRNA-34a protects myocardial cells against ischemia–reperfusion injury through inhibiting autophagy via regulating TNFα expression

2018 ◽  
Vol 96 (3) ◽  
pp. 349-354 ◽  
Author(s):  
Haifeng Shao ◽  
Lili Yang ◽  
Li Wang ◽  
Bozan Tang ◽  
Jian Wang ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Heart Tissue ◽  
Neonatal Rat ◽  
Cell Counting ◽  
In Vivo Model ◽  
Myocardial Cells ◽  
Rat Cardiomyocytes ◽  
Cardiac Tissues

Background: ischemia–reperfusion (I/R) is a consequence of restored blood supply after myocardial infarction. Myocardial I/R injury can be alleviated by reducing autophagy in heart tissue. MicroRNA-34a (miR-34a) has been shown to regulate autophagy in a renal model of I/R, but it is not known whether it can protect cardiac tissues from I/R injury. This study investigated how miR-34a protects myocardial cells from I/R injury by inhibiting autophagy via regulation of tumor necrosis factor α (TNFα). Methods: we constructed an I/R model in vivo using Langendorff perfusion, and we constructed an in vivo model by treating neonatal rat cardiomyocytes (NRCMs) with hypoxia–reoxygenation (H/R method). Transfected adenoviral-overexpressed miR-34a mimics and controlled NRCMs after H/R. We analyzed cell viability using the MTT assay and a cell counting kit-8 (CCK-8) assay. Changes in the rate of apoptosis were detected by flow cytometry. We investigated the effect mechanisms of miR-34a with Western blot and luciferase assays. Results: miR-34a expression decreased after in vivo reperfusion of the myocardial cells and heart tissues of neonatal rats. MiR-34a reduced apoptosis of the NRCMs and autophagy levels, simultaneously, after H/R injury. Further, miR-34a decreased the expression of Lc3-II and p62, indicating that miR-34a reduces myocardial I/R injury by decreasing TNFα expression. Conclusion: miR-34a can inhibit autophagy levels after I/R by targeting TNFα, thereby reducing myocardial injury.

scholarly journals Activation ofβ-Adrenoceptors by Dobutamine May Induce a Higher Expression of Peroxisome Proliferator-Activated Receptorsδ(PPARδ) in Neonatal Rat Cardiomyocytes

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Ming-Ting Chou ◽  
Shih-Hsiang Lo ◽  
Kai-Chun Cheng ◽  
Yin-Xiao Li ◽  
Li-Jen Chen ◽  
...  
Keyword(s):  
Troponin I ◽  
Cardiac Cells ◽  
Cardiac Contraction ◽  
Neonatal Rat ◽  
Peroxisome Proliferator ◽  
Emergency Setting ◽  
Dependent Manner ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Cardiomyocytes ◽  
Peroxisome Proliferator Activated Receptors

Recent evidence showed the role of peroxisome proliferator-activated receptors (PPARs) in cardiac function. Cardiac contraction induced by various agents is critical in restoring the activity of peroxisome proliferator-activated receptorsδ(PPARδ) in cardiac myopathy. Because dobutamine is an agent widely used to treat heart failure in emergency setting, this study is aimed to investigate the change of PPARδin response to dobutamine. Neonatal rat cardiomyocytes were used to examine the effects of dobutamine on PPARδexpression levels and cardiac troponin I (cTnI) phosphorylation via Western blotting analysis. We show that treatment with dobutamine increased PPARδexpression and cTnI phosphorylation in a time- and dose-dependent manner in neonatal rat cardiomyocytes. These increases were blocked by the antagonist ofβ1-adrenoceptors. Also, the action of dobutamine was related to the increase of calcium ions and diminished by chelating intracellular calcium. Additionally, dobutamine-induced action was reduced by the inhibition of downstream messengers involved in this calcium-related pathway. Moreover, deletion of PPARδusing siRNA generated the reduction of cTnI phosphorylation in cardiomyocytes treated with dobutamine. Thus, we concluded that PPARδis increased by dobutamine in cardiac cells.

scholarly journals Adenine Nucleotide Translocase 1 Expression Is Coupled to the HSP27-Mediated TLR4 Signaling in Cardiomyocytes

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1588 ◽  
Author(s):  
Julia Winter ◽  
Elke Hammer ◽  
Jacqueline Heger ◽  
Heinz-Peter Schultheiss ◽  
Ursula Rauch ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Adenine Nucleotide ◽  
Heart Tissue ◽  
Neonatal Rat ◽  
Adenine Nucleotide Translocase ◽  
Inner Mitochondrial Membrane ◽  
Tlr4 Signaling ◽  
Rat Cardiomyocytes

The cardiac-specific overexpression of the adenine nucleotide translocase 1 (ANT1) has cardioprotective effects in various experimental heart disease models. Here, we analyzed the link between ANT1 expression and heat shock protein 27 (HSP27)-mediated toll-like receptor 4 (TLR4) signaling, which represents a novel communication pathway between mitochondria and the extracellular environment. The interaction between ANT1 and HSP27 was identified by co-immunoprecipitation from neonatal rat cardiomyocytes. ANT1 transgenic (ANT1-TG) cardiomyocytes demonstrated elevated HSP27 expression levels. Increased levels of HSP27 were released from the ANT1-TG cardiomyocytes under both normoxic and hypoxic conditions. Extracellular HSP27 stimulated TLR4 signaling via protein kinase B (AKT). The HSP27-mediated activation of the TLR4 pathway was more pronounced in ANT1-TG cardiomyocytes than in wild-type (WT) cardiomyocytes. HSP27-specific antibodies inhibited TLR4 activation and the expression of HSP27. Inhibition of the HSP27-mediated TLR4 signaling pathway with the TLR4 inhibitor oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) reduced the mitochondrial membrane potential (∆ψm) and increased caspase 3/7 activity, which are both markers for cell stress. Conversely, treating cardiomyocytes with recombinant HSP27 protein stimulated TLR4 signaling, induced HSP27 and ANT1 expression, and stabilized the mitochondrial membrane potential. The activation of HSP27 signaling was verified in ischemic ANT1-TG heart tissue, where it correlated with ANT1 expression and the tightness of the inner mitochondrial membrane. Our study shows a new mechanism by which ANT1 is part of the cardioprotective HSP27-mediated TLR4 signaling.

Abstract 288: Rnd3/RhoE Regulates Cardiac Ryanodine Receptor Type 2 Stability

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
xiangsheng yang ◽  
Tiannan Wang ◽  
Xiaojing Yue ◽  
Xander H.T. Wehrens ◽  
Jiang Chang
Keyword(s):  
Ryanodine Receptor ◽  
Rho Gtpase ◽  
Single Channel ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Receptor Type ◽  
Post Translational Modification ◽  
Rat Cardiomyocytes ◽  
Protein Levels

Rationale: Rnd3, a small Rho GTPase, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration and proliferation. The biological function of Rnd3 in the heart remains unexplored. Objective: To define the functional role of the Rnd3 gene in the animal heart and investigate the associated molecular mechanism. Methods and Results: By loss-of-function approaches, we discovered a new role in which Rnd3 stabilizes the ryanodine receptor type 2 (RyR2) Ca 2+ release channel. Genetic deletion of Rnd3 in mice resulted in embryonic lethality with heart failure and arrhythmia. Both Rnd3 -/- embryonic and Rnd3 +/- adult cardiomyocytes showed severe Ca 2+ leakage. Single channel assessment showed the destabilized RyR2 channel, and this irregular spontaneous Ca 2+ release was curtailed by protein kinase A (PKA) inhibitor treatment. Further studies found that RyR2 protein was hyperphosphorylated by PKA in the mutant heart. Remarkable increases in the PKA activity along with elevated cyclic adenosine monophosphate levels were detected in vivo in Rnd3-null embryos and in vitro in neonatal rat cardiomyocytes and non-cardiac cell lines with Rnd3 knockdown. Moreover, we found increasing β 2 -adrenergic receptor (β 2 AR) protein levels, but no correlated mRNA changes in both the Rnd3-null heart and non-cardiac cells with Rnd3 knockdown. Immunoprecipitation analysis demonstrated that Rnd3 and β 2 AR physically interacted. Multiple post-translational modification analyses of β 2 AR revealed that downregulation of Rnd3 attenuated β 2 AR protein lysosomal targeting and ubiquitination, which in turn resulted in the elevation of β 2 AR protein levels contributing to the activation of PKA signaling. Rnd3 deficiency had no effects on the hydroxylation- and sumoylation-mediated β 2 AR protein degradation. Conclusion: Rnd3 is a unique stabilizer of RyR2 that impacts intracellular Ca 2+ handling in the heart.

Action of chelators in iron-loaded cardiac cells: accessibility to intracellular labile iron and functional consequences

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 3195-3203 ◽  
Author(s):  
Hava Glickstein ◽  
Rinat Ben El ◽  
Gabi Link ◽  
William Breuer ◽  
Abraham M. Konijn ◽  
...  
Keyword(s):  
Iron Overload ◽  
Plasma Concentrations ◽  
Cardiac Contractility ◽  
Iron Chelation ◽  
Time Lapse ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Cardiac Damage ◽  
Rat Cardiomyocytes ◽  
Labile Iron

Abstract Labile iron in hemosiderotic plasma and tissue are sources of iron toxicity. We compared the iron chelators deferoxamine, deferiprone, and deferasirox as scavengers of labile iron in plasma and cardiomyocytes at therapeutic concentrations. This comprised chelation of labile plasma iron (LPI) in samples from thalassemia patients; extraction of total cellular iron; accessing labile iron accumulated in organelles and preventing formation of reactive-oxidant species; and restoring impaired cardiac contractility. Neonatal rat cardiomyocytes were used for monitoring chelator extraction of LCI (labile cell iron) as 59Fe; assessing in situ cell iron chelation by epifluorescence microscope imaging using novel fluorescent sensors for iron and reactive oxygen species (ROS) selectively targeted to organelles, and monitoring contractility by time-lapse microscopy. At plasma concentrations attained therapeutically, all 3 chelators eliminated LPI but the orally active chelators rapidly gained access to the LCI pools of cardiomyocytes, bound labile iron, attenuated ROS formation, extracted accumulated iron, and restored contractility impaired by iron overload. The effect of deferoxamine at therapeutically relevant concentrations was primarily by elimination of LPI. The rapid accessibility of the oral chelators deferasirox and deferiprone to intracellular labile iron compartments renders them potentially efficacious for protection from and possibly reversal of cardiac damage induced by iron overload.

scholarly journals Stilbene derivative as a photosensitive compound to control the excitability of neonatal rat cardiomyocytes

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Sheida R. Frolova ◽  
Vasili S. Gorbunov ◽  
Natalia S. Shubina ◽  
Alexander M. Perepukhov ◽  
Sandaara G. Romanova ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Structural Analog ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Light Illumination ◽  
Neural Cells ◽  
Trans Form ◽  
Rat Cardiomyocytes ◽  
Stilbene Derivative ◽  
Voltage Gated Ion Channels

Abstract Substances that can be used as photosensitizers for cardiac tissue are very helpful in modeling various excitation patterns in a cardiac tissue culture and may have prospective use in the temporary and permanent ablation of unwanted excitation sources in the heart. The aim of the present work is to study the effect of stilbene derivative c-TAB (2- {4- [(E) -2- (4-ethoxyphenyl) vinyl] phenoxy} ethyl) trimethylammonium bromide) on the cardiomyocyte layers and voltage-gated ion channels in cardiac cells. C-TAB is a structural analog to AzoTAB, reported previously as a photoswitch for cardiac and neural cells, in which the azobenzene moiety is replaced by a stilbene grouping. Such a replacement makes c-TAB less toxic to living cells. c-TAB has been shown to successfully inhibit excitation in cardiac cells in both trans- and cis- forms. The excitation inhibition of cardiac cells under c-TAB is reversible and can be overturned easily by washing out the c-TAB; however, not by light illumination. The irradiation of cardiac cells with near-UV, when the trans- form of c-TAB is applied, changes reversible inhibition to a permanent one that cannot be overturned by a washout.

scholarly journals The Adipokine Chemerin Induces Apoptosis in Cardiomyocytes

2015 ◽  
Vol 37 (1) ◽  
pp. 176-192 ◽  
Author(s):  
Diego Rodríguez-Penas ◽  
Sandra Feijóo-Bandín ◽  
Vanessa García-Rúa ◽  
Ana Mosquera-Leal ◽  
Darío Durán ◽  
...  
Keyword(s):  
Western Blot ◽  
Vital Staining ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Caspase 9 ◽  
Rat Cardiomyocytes ◽  
Akt Phosphorylation ◽  
Protein Levels ◽  
Tnf Α ◽  
Hoechst Dye

Background: The adipokine chemerin has been associated with cardiovascular disease. We investigated the effects of chemerin on viability and intracellular signalling in murine cardiomyocytes, and the effects of insulin and TNF-α on cardiomyocyte chemerin production. Methods: Hoechst dye vital staining and cell cycle analysis were used to analyse the viability of murine cardiac cells in culture. Western blot was used to explore the phosphorylation of AKT and caspase-9 activity in neonatal rat cardiomyocytes and HL-1 cells. Finally, RT-qPCR, ELISA and western blot were performed to examine chemerin and CMKLR1 expression after insulin and TNF-α treatment in cardiac cells. Results: Chemerin treatment increased apoptosis, reduced phosphorylation of AKT at Thr308 and increased caspase-9 activity in murine cardiomyocytes. Insulin treatment lowered chemerin and CMKLR1 mRNA and protein levels, and the amount of chemerin in the cell media, while TNF-α treatment increased chemerin mRNA and protein levels but decreased expression of the CMKLR1 gene. Conclusion: Chemerin induces apoptosis, reduces AKT phosphorylation and increases the cleavage of caspase-9 in murine cardiomyocytes. The expression of chemerin is regulated by important metabolic (insulin) and inflammatory (TNF-α) mediators at cardiac level. Our results suggest that chemerin could play a role in the physiopathology of cardiac diseases.

scholarly journals Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

2016 ◽  
Vol 310 (9) ◽  
pp. E782-E794 ◽  
Author(s):  
Laura Pentassuglia ◽  
Philippe Heim ◽  
Sonia Lebboukh ◽  
Christian Morandi ◽  
Lifen Xu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Ventricular Myocytes ◽  
Cardiac Development ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Akt Inhibitor ◽  
Protective Function ◽  
Rat Cardiomyocytes

Nrg1β is critically involved in cardiac development and also maintains function of the adult heart. Studies conducted in animal models showed that it improves cardiac performance under a range of pathological conditions, which led to its introduction in clinical trials to treat heart failure. Recent work also implicated Nrg1β in the regenerative potential of neonatal and adult hearts. The molecular mechanisms whereby Nrg1β acts in cardiac cells are still poorly understood. In the present study, we analyzed the effects of Nrg1β on glucose uptake in neonatal rat ventricular myocytes and investigated to what extent mTOR/Akt signaling pathways are implicated. We show that Nrg1β enhances glucose uptake in cardiomyocytes as efficiently as IGF-I and insulin. Nrg1β causes phosphorylation of ErbB2 and ErbB4 and rapidly induces the phosphorylation of FAK (Tyr861), Akt (Thr308 and Ser473), and its effector AS160 (Thr642). Knockdown of ErbB2 or ErbB4 reduces Akt phosphorylation and blocks the glucose uptake. The Akt inhibitor VIII and the PI3K inhibitors LY-294002 and Byl-719 abolish Nrg1β-induced phosphorylation and glucose uptake. Finally, specific mTORC2 inactivation after knockdown of rictor blocks the Nrg1β-induced increases in Akt-p-Ser473 but does not modify AS160-p-Thr642 or the glucose uptake responses to Nrg1β. In conclusion, our study demonstrates that Nrg1β enhances glucose uptake in cardiomyocytes via ErbB2/ErbB4 heterodimers, PI3Kα, and Akt. Furthermore, although Nrg1β activates mTORC2, the resulting Akt-Ser473 phosphorylation is not essential for glucose uptake induction. These new insights into pathways whereby Nrg1β regulates glucose uptake in cardiomyocytes may contribute to the understanding of its regenerative capacity and protective function in heart failure.

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