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1.
Am J Physiol Endocrinol Metab ; 310(9): E782-94, 2016 May 01.
Article in English | MEDLINE | ID: mdl-26979522

ABSTRACT

Nrg1ß 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 Nrg1ß in the regenerative potential of neonatal and adult hearts. The molecular mechanisms whereby Nrg1ß acts in cardiac cells are still poorly understood. In the present study, we analyzed the effects of Nrg1ß on glucose uptake in neonatal rat ventricular myocytes and investigated to what extent mTOR/Akt signaling pathways are implicated. We show that Nrg1ß enhances glucose uptake in cardiomyocytes as efficiently as IGF-I and insulin. Nrg1ß causes phosphorylation of ErbB2 and ErbB4 and rapidly induces the phosphorylation of FAK (Tyr(861)), Akt (Thr(308) and Ser(473)), and its effector AS160 (Thr(642)). 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 Nrg1ß-induced phosphorylation and glucose uptake. Finally, specific mTORC2 inactivation after knockdown of rictor blocks the Nrg1ß-induced increases in Akt-p-Ser(473) but does not modify AS160-p-Thr(642) or the glucose uptake responses to Nrg1ß. In conclusion, our study demonstrates that Nrg1ß enhances glucose uptake in cardiomyocytes via ErbB2/ErbB4 heterodimers, PI3Kα, and Akt. Furthermore, although Nrg1ß activates mTORC2, the resulting Akt-Ser(473) phosphorylation is not essential for glucose uptake induction. These new insights into pathways whereby Nrg1ß regulates glucose uptake in cardiomyocytes may contribute to the understanding of its regenerative capacity and protective function in heart failure.


Subject(s)
Glucose/metabolism , Heart Ventricles/cytology , Multiprotein Complexes/metabolism , Myocytes, Cardiac/drug effects , Neuregulin-1/pharmacology , Phosphatidylinositol 3-Kinases/drug effects , Proto-Oncogene Proteins c-akt/drug effects , TOR Serine-Threonine Kinases/metabolism , Animals , Animals, Newborn , Blotting, Western , Gene Knockdown Techniques , Hypoglycemic Agents/pharmacology , Immunoprecipitation , Insulin/pharmacology , Insulin-Like Growth Factor I/pharmacology , Mechanistic Target of Rapamycin Complex 2 , Mice , Mice, Inbred C57BL , Myocytes, Cardiac/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation/drug effects , Protein Biosynthesis/drug effects , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering , Rats , Receptor, ErbB-2/drug effects , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptor, ErbB-4/drug effects , Receptor, ErbB-4/genetics , Receptor, ErbB-4/metabolism
2.
Cardiovasc Res ; 109(1): 103-14, 2016 Jan 01.
Article in English | MEDLINE | ID: mdl-26598511

ABSTRACT

AIMS: Mammalian target of rapamycin (mTOR), a central regulator of growth and metabolism, has tissue-specific functions depending on whether it is part of mTOR complex 1 (mTORC1) or mTORC2. We have previously shown that mTORC1 is required for adaptive cardiac hypertrophy and maintenance of function under basal and pressure-overload conditions. In the present study, we aimed to identify functions of mTORC2 in the heart. METHODS AND RESULTS: Using tamoxifen-inducible cardiomyocyte-specific gene deletion, we generated mice deficient for cardiac rapamycin-insensitive companion of mTOR (rictor), an essential and specific component of mTORC2. Under basal conditions, rictor deficiency did not affect cardiac growth and function in young mice and also had no effects in adult mice. However, transverse aortic constriction caused dysfunction in the rictor-deficient hearts, whereas function was maintained in controls after 1 week of pressure overload. Adaptive increases in cardiac weight and cardiomyocyte cross-sectional area, fibrosis, and hypertrophic and metabolic gene expression were not different between the rictor-deficient and control mice. In control mice, maintained function was associated with increased protein levels of rictor, protein kinase C (PKC)ßII, and PKCδ, whereas rictor ablation abolished these increases. Rictor deletion also significantly decreased PKCε at baseline and after pressure overload. Our data suggest that reduced PKCε and the inability to increase PKCßII and PKCδ abundance are, in accordance with their known function, responsible for decreased contractile performance of the rictor-deficient hearts. CONCLUSION: Our study demonstrates that mTORC2 is implicated in maintaining contractile function of the pressure-overloaded male mouse heart.


Subject(s)
Cardiomegaly/physiopathology , Multiprotein Complexes/physiology , TOR Serine-Threonine Kinases/physiology , Ventricular Function/physiology , Animals , Apoptosis , Carrier Proteins/physiology , Fibrosis , Male , Mechanistic Target of Rapamycin Complex 2 , Mice , Mice, Inbred C57BL , Myocardium/pathology , Phosphoproteins/physiology , Phosphorylation , Protein Kinase C/analysis , Proto-Oncogene Proteins c-akt/metabolism , Rapamycin-Insensitive Companion of mTOR Protein , Signal Transduction
3.
PLoS One ; 8(2): e55741, 2013.
Article in English | MEDLINE | ID: mdl-23437060

ABSTRACT

AIMS: Recombinant Neuregulin (NRG)-1ß has multiple beneficial effects on cardiac myocytes in culture, and has potential as a clinical therapy for heart failure (HF). A number of factors may influence the effect of NRG-1ß on cardiac function via ErbB receptor coupling and expression. We examined the effect of the NRG-1ß isoform, glial growth factor 2 (GGF2), in rats with myocardial infarction (MI) and determined the impact of high-fat diet as well as chronicity of disease on GGF2 induced improvement in left ventricular systolic function. Potential mechanisms for GGF2 effects on the remote myocardium were explored using microarray and proteomic analysis. METHODS AND RESULTS: Rats with MI were randomized to receive vehicle, 0.625 mg/kg, or 3.25 mg/kg GGF2 in the presence and absence of high-fat feeding beginning at day 7 post-MI and continuing for 4 weeks. Residual left ventricular (LV) function was improved in both of the GGF2 treatment groups compared with the vehicle treated MI group at 4 weeks of treatment as assessed by echocardiography. High-fat diet did not prevent the effects of high dose GGF2. In experiments where treatment was delayed until 8 weeks after MI, high but not low dose GGF2 treatment was associated with improved systolic function. mRNA and protein expression analysis of remote left ventricular tissue revealed a number of changes in myocardial gene and protein expression altered by MI that were normalized by GGF2 treatment, many of which are involved in energy production. CONCLUSIONS: This study demonstrates that in rats with MI induced systolic dysfunction, GGF2 treatment improves cardiac function. There are differences in sensitivity of the myocardium to GGF2 effects when administered early vs. late post-MI that may be important to consider in the development of GGF2 in humans.


Subject(s)
Gene Expression Regulation/drug effects , Myocardial Infarction/genetics , Myocardial Infarction/physiopathology , Neuregulin-1/pharmacology , Neuregulin-1/therapeutic use , Ventricular Function, Left/drug effects , Animals , Diet, High-Fat , Electrocardiography , Fibrosis , Glucose/metabolism , Heart Ventricles/drug effects , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Humans , Injections, Intravenous , Male , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/drug therapy , Myocardium/metabolism , Myocardium/pathology , Neuregulin-1/administration & dosage , Neuregulin-1/metabolism , Organ Size/drug effects , Oxidative Stress/drug effects , Positron-Emission Tomography , Protein Isoforms/metabolism , Proteome/metabolism , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Receptor Protein-Tyrosine Kinases/metabolism , Tissue Survival/drug effects , Ultrasonography
4.
Biochim Biophys Acta ; 1833(4): 909-16, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23261977

ABSTRACT

Neuregulin (Nrg)/ErbB and integrin signaling pathways are critical for the normal function of the embryonic and adult heart. Both systems activate several downstream signaling pathways, with different physiological outputs: cell survival, fibrosis, excitation-contraction coupling, myofilament structure, cell-cell and cell-matrix interaction. Activation of ErbB2 by Nrg1ß in cardiomycytes or its overexpression in cancer cells induces phosphorylation of FAK (Focal Adhesion Kinase) at specific sites with modulation of survival, invasion and cell-cell contacts. FAK is also a critical mediator of integrin receptors, converting extracellular matrix alterations into intracellular signaling. Systemic FAK deletion is lethal and is associated with left ventricular non-compaction whereas cardiac restriction in adult hearts is well tolerated. Nevertheless, these hearts are more susceptible to stress conditions like trans-aortic constriction, hypertrophy, and ischemic injury. As FAK is both downstream and specifically activated by integrins and Nrg-1ß, here we will explore the role of FAK in the heart as a protective factor and as possible mediator of the crosstalk between the ErbB and Integrin receptors. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.


Subject(s)
Cardiomegaly/metabolism , Focal Adhesion Protein-Tyrosine Kinases/genetics , Integrins/genetics , Myocardial Ischemia/metabolism , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Oncogene Proteins v-erbB/genetics , Cardiomegaly/genetics , Cardiomegaly/pathology , Cell Communication , Extracellular Matrix/metabolism , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Gene Expression Regulation , Humans , Integrins/metabolism , Isoenzymes/genetics , Isoenzymes/metabolism , Myocardial Ischemia/genetics , Myocardial Ischemia/pathology , Myocardium/pathology , Myocytes, Cardiac/pathology , Neuregulin-1/genetics , Neuregulin-1/metabolism , Oncogene Proteins v-erbB/metabolism , Protein Binding , Signal Transduction
5.
Curr Heart Fail Rep ; 9(3): 211-8, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22752360

ABSTRACT

Damage to heart cells leading to heart failure is a known complication of well-established cancer therapies including anthracycline antibiotics and radiation therapy, and the cardiovascular complications of these therapies has been controlled in large part through dose limitations and modifications of delivery methods. Recent research into the cellular and molecular mechanisms for the cardiovascular effects of these therapies may lead to other cardioprotective strategies that improve effectiveness of cancer treatments. Newer cancer therapies that have been developed based upon specifically targeting oncogene signaling also have been associated with heart failure. Rapid development of a detailed understanding of how these agents cause cardiac dysfunction promises to improve outcomes in cancer patients, as well as stimulate concepts of cardiovascular homeostasis that will likely accelerate development of cardiovascular therapies.


Subject(s)
Antibiotics, Antineoplastic/adverse effects , Antineoplastic Agents/adverse effects , Heart Failure/chemically induced , Myocytes, Cardiac/drug effects , Anthracyclines/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Benzenesulfonates/adverse effects , Daunorubicin/adverse effects , Doxorubicin/adverse effects , Humans , Indoles/adverse effects , Myocardial Contraction/drug effects , Niacinamide/analogs & derivatives , Phenylurea Compounds , Pyridines/adverse effects , Pyrroles/adverse effects , Sorafenib , Sunitinib , Trastuzumab
6.
PLoS One ; 7(4): e35743, 2012.
Article in English | MEDLINE | ID: mdl-22532871

ABSTRACT

Doxorubicin (Adriamycin) is an effective anti-cancer drug, but its clinical usage is limited by a dose-dependent cardiotoxicity characterized by widespread sarcomere disarray and loss of myofilaments. Cardiac ankyrin repeat protein (CARP, ANKRD1) is a transcriptional regulatory protein that is extremely susceptible to doxorubicin; however, the mechanism(s) of doxorubicin-induced CARP depletion and its specific role in cardiomyocytes have not been completely defined. We report that doxorubicin treatment in cardiomyocytes resulted in inhibition of CARP transcription, depletion of CARP protein levels, inhibition of myofilament gene transcription, and marked sarcomere disarray. Knockdown of CARP with small interfering RNA (siRNA) similarly inhibited myofilament gene transcription and disrupted cardiomyocyte sarcomere structure. Adenoviral overexpression of CARP, however, was unable to rescue the doxorubicin-induced sarcomere disarray phenotype. Doxorubicin also induced depletion of the cardiac transcription factor GATA4 in cardiomyocytes. CARP expression is regulated in part by GATA4, prompting us to examine the relationship between GATA4 and CARP in cardiomyocytes. We show in co-transfection experiments that GATA4 operates upstream of CARP by activating the proximal CARP promoter. GATA4-siRNA knockdown in cardiomyocytes inhibited CARP expression and myofilament gene transcription, and induced extensive sarcomere disarray. Adenoviral overexpression of GATA4 (AdV-GATA4) in cardiomyocytes prior to doxorubicin exposure maintained GATA4 levels, modestly restored CARP levels, and attenuated sarcomere disarray. Interestingly, siRNA-mediated depletion of CARP completely abolished the Adv-GATA4 rescue of the doxorubicin-induced sarcomere phenotype. These data demonstrate co-dependent roles for GATA4 and CARP in regulating sarcomere gene expression and maintaining sarcomeric organization in cardiomyocytes in culture. The data further suggests that concurrent depletion of GATA4 and CARP in cardiomyocytes by doxorubicin contributes in large part to myofibrillar disarray and the overall pathophysiology of anthracycline cardiomyopathy.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Cardiomyopathies/metabolism , Doxorubicin/pharmacology , GATA4 Transcription Factor/metabolism , Muscle Proteins/metabolism , Myocytes, Cardiac/drug effects , Nuclear Proteins/metabolism , Repressor Proteins/metabolism , Sarcomeres/drug effects , Signal Transduction/physiology , Animals , Cardiomyopathies/chemically induced , GATA4 Transcription Factor/genetics , Male , Muscle Proteins/genetics , Myocytes, Cardiac/metabolism , Nuclear Proteins/genetics , Promoter Regions, Genetic , Rats , Rats, Sprague-Dawley , Repressor Proteins/genetics , Sarcomeres/metabolism
7.
Biochem Biophys Res Commun ; 418(1): 116-21, 2012 Feb 03.
Article in English | MEDLINE | ID: mdl-22244893

ABSTRACT

The intracellular domain of ErbB4 receptor tyrosine kinase is known to translocate to the nucleus of cells where it can regulate p53 transcriptional activity. The purpose of this study was to examine whether ErbB4 can localize to the nucleus of adult rat ventricular myocytes (ARVM), and regulate p53 in these cells. We demonstrate that ErbB4 does locate to the nucleus of cardiac myocytes as a full-length protein, although nuclear location occurs as a full-length protein that does not require Protein Kinase C or γ-secretase activity. Consistent with this we found that only the non-cleavable JM-b isoform of ErbB4 is expressed in ARVM. Doxorubicin was used to examine ErbB4 role in regulation of a DNA damage response in ARVM. Doxorubicin induced p53 and p21 was suppressed by treatment with AG1478, an EGFR and ErbB4 kinase inhibitor, or suppression of ErbB4 expression with small interfering RNA. Thus ErbB4 localizes to the nucleus as a full-length protein, and plays a role in the DNA damage response induced by doxorubicin in cardiac myocytes.


Subject(s)
Cell Nucleus/enzymology , DNA Damage , ErbB Receptors/metabolism , Myocytes, Cardiac/enzymology , Animals , Cell Nucleus/drug effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Doxorubicin/pharmacology , ErbB Receptors/antagonists & inhibitors , Heart Ventricles/cytology , Mice , Myocytes, Cardiac/drug effects , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Rats , Receptor, ErbB-4 , Tumor Suppressor Protein p53/metabolism , Tyrphostins/pharmacology
8.
Am J Physiol Heart Circ Physiol ; 300(4): H1311-9, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21239627

ABSTRACT

Endothelial progenitor cells (EPCs) are mobilized into the vascular space and home to damaged tissues, where they promote repair in part through a process of angiogenesis. Neuregulins (NRGs) are ligands in the epidermal growth factor family that signal through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3, and erbB4) and regulate endothelial cell biology, promoting angiogenesis. Stimuli such as ischemia and exercise that promote EPC mobilization also induce cleavage and release of transmembrane NRG from cardiac microvascular endothelial cells (CMECs). We hypothesized that NRG/erbB signaling may regulate EPC biology. Using an embryonic (e)EPC cell line that homes to and repairs injured myocardium, we were able to detect erbB2 and erbB3 transcripts. Identical receptor expression was found in EPCs isolated from rat bone marrow and human whole blood. NRG treatment of eEPCs induces phosphorylation of kinases including Akt, GSK-3ß, and Erk1/2 and the nuclear accumulation and transcriptional activation of ß-catenin. NRG does not induce eEPC proliferation or migration but does protect eEPCs against serum deprivation-induced apoptosis. These results suggest a role for tissue-derived NRG in the regulation of EPC survival.


Subject(s)
Embryonic Stem Cells/physiology , Neuregulin-1/physiology , Animals , Bone Marrow Cells/metabolism , Cell Survival , Cells, Cultured , Embryonic Stem Cells/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Leukocytes, Mononuclear/metabolism , Mice , Neuregulin-1/pharmacology , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Receptor, ErbB-2/biosynthesis , Receptor, ErbB-3/biosynthesis , beta Catenin/metabolism
9.
Prog Cardiovasc Dis ; 53(2): 105-13, 2010.
Article in English | MEDLINE | ID: mdl-20728697

ABSTRACT

Anthracycline antibiotics have saved the lives of many cancer victims in the 50 plus years since their discovery. A major limitation of their use is the dose-limiting cardiotoxicity. Efforts focusing on understanding the biochemical basis for anthracycline cardiac effects have provided several strategies currently in clinical use: limit dose exposure, encapsulate anthracyclines in liposomes to reduce myocardial uptake, administer concurrently with the iron chelator dexrazoxane to reduce free iron-catalyzed reactive oxygen species formation; and modify anthracycline structure in an effort to reduce myocardial toxicity. Despite these efforts, anthracycline-induced heart failure continues to occur with consequences for both morbidity and mortality. Our inability to predict and prevent anthracycline cardiotoxicity is, in part, due to the fact that the molecular and cellular mechanisms remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes in vitro and small animals in vivo have demonstrated several forms of cardiac injury, and it remains unclear how these translate to the clinical setting. Given the clinical evidence that myocyte death occurs after anthracycline exposure in the form of elevations in serum troponin, myocyte cell death seems to be a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular "sarcopenia" characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. There is now evidence that erbB2 signaling in response to the ligand neuregulin regulates anthracycline uptake into cells via the multidrug-resistance protein. Therefore, up-regulation of cardiac neuregulin signaling may be one strategy to limit myocardial anthracycline injury. Moreover, assessing an individual's risk for anthracycline injury may be improved by having some measure of endogenous activity of this and other myocardial protective signals.


Subject(s)
Anthracyclines/adverse effects , Antibiotics, Antineoplastic/adverse effects , Heart Diseases/chemically induced , Myocytes, Cardiac/drug effects , Neoplasms/drug therapy , Animals , Cell Death , Heart Diseases/metabolism , Heart Diseases/pathology , Heart Diseases/prevention & control , Humans , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Receptor, ErbB-2/metabolism , Sarcomeres/drug effects , Sarcomeres/metabolism , Signal Transduction/drug effects
10.
Circ Res ; 106(6): 1022-34, 2010 Apr 02.
Article in English | MEDLINE | ID: mdl-20360265

ABSTRACT

The race for a cure to cancer continues, fueled by unprecedented discoveries of fundamental biology underlying carcinogenesis and tumorigenesis. The expansion of the target list and tools to approach them is moving the oncology community extraordinarily rapidly to clinical trials, bringing new hope for cancer patients. This effort is also propelling biological discoveries in cardiovascular research, because many of the targets being explored in cancer play fundamental roles in the heart and vasculature. The combined efforts of cardiovascular and cancer biologists, along with clinical investigators in these fields, will be needed to understand how to safely exploit these efforts. Here, we discuss a few of the many research foci in oncology where we believe such collaboration will be particularly important.


Subject(s)
Antineoplastic Agents/adverse effects , Cardiovascular Diseases/chemically induced , Cardiovascular System/drug effects , Drugs, Investigational/adverse effects , Animals , Apoptosis/drug effects , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Cardiovascular System/metabolism , DNA Repair/drug effects , Epigenesis, Genetic/drug effects , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Focal Adhesions/drug effects , Focal Adhesions/metabolism , Humans , Integrins/metabolism , Molecular Chaperones/metabolism , Paracrine Communication/drug effects , Proteasome Endopeptidase Complex/drug effects , Proteasome Endopeptidase Complex/metabolism , Risk Assessment , Signal Transduction/drug effects
11.
Exp Cell Res ; 315(7): 1302-12, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19331811

ABSTRACT

Inhibition of ErbB2 (HER2) with monoclonal antibodies, an effective therapy in some forms of breast cancer, is associated with cardiotoxicity, the pathophysiology of which is poorly understood. Recent data suggest, that dual inhibition of ErbB1 (EGFR) and ErbB2 signaling is more efficient in cancer therapy, however, cardiac safety of this therapeutic approach is unknown. We therefore tested an ErbB1-(CGP059326) and an ErbB1/ErbB2-(PKI166) tyrosine kinase inhibitor in an in-vitro system of adult rat ventricular cardiomyocytes and assessed their effects on 1. cell viability, 2. myofibrillar structure, 3. contractile function, and 4. MAPK- and Akt-signaling alone or in combination with Doxorubicin. Neither CGP nor PKI induced cardiomyocyte necrosis or apoptosis. PKI but not CGP caused myofibrillar structural damage that was additive to that induced by Doxorubicin at clinically relevant doses. These changes were associated with an inhibition of excitation-contraction coupling. PKI but not CGP decreased p-Erk1/2, suggesting a role for this MAP-kinase signaling pathway in the maintenance of myofibrils. These data indicate that the ErbB2 signaling pathway is critical for the maintenance of myofibrillar structure and function. Clinical studies using ErbB2-targeted inhibitors for the treatment of cancer should be designed to include careful monitoring for cardiac dysfunction.


Subject(s)
Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Myofibrils/metabolism , Protein Kinase Inhibitors/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Animals , Antibiotics, Antineoplastic/pharmacology , Calcium/metabolism , Cell Death/physiology , Cells, Cultured , Connectin , Doxorubicin/pharmacology , ErbB Receptors/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , GATA4 Transcription Factor/metabolism , Male , Mice , Mitochondria/metabolism , Muscle Proteins/metabolism , Myocardial Contraction/drug effects , Myocardial Contraction/physiology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Myofibrils/ultrastructure , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Wistar , Receptor, ErbB-2/metabolism , Receptor, ErbB-4 , Signal Transduction/physiology
12.
Exp Cell Res ; 315(4): 627-37, 2009 Feb 15.
Article in English | MEDLINE | ID: mdl-18801360

ABSTRACT

Products of the Neuregulin-1 (Nrg-1) gene, along with the ErbB family of receptor tyrosine kinases through which Nrg-1 ligands signal, play a critical role during cardiovascular development. Through studies of genetically manipulated mice, as well as studies in cells isolated from adult hearts, it appears that Nrg-1/ErbB signaling is an essential paracrine mediator of cell-cell interactions that not only regulates tissue organization during development, but also helps to maintain cardiac function throughout an organism's life. Studies in cells isolated from the heart demonstrate that Nrg-1 can activate a number of signaling pathways, which mediate cellular adaptations to stress in the myocardium. These observations provide insight as to why ErbB2-targeted cancer treatments have deleterious effects on cardiac function in some cancer patients. Moreover emerging data suggest that Nrg-1 ligands might be useful clinically to restore cardiac function after cardiac injury. In this review we will attempt to synthesize the literature behind this rapidly growing and exciting area of research.


Subject(s)
Myocardium/metabolism , Neuregulin-1/physiology , Receptor, ErbB-2/metabolism , Signal Transduction , Animals , Heart/growth & development , Humans , Myocytes, Cardiac/metabolism
13.
Cardiovasc Toxicol ; 7(2): 114-21, 2007.
Article in English | MEDLINE | ID: mdl-17652815

ABSTRACT

The molecular and cellular mechanisms that cause cumulative dose-dependent anthracycline-cardiotoxicity remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes inA vitro have demonstrated several forms of cellular injury. Cell death in response to anthracyclines can be observed by one of several mechanisms including apoptosis and necrosis. Cell death by apoptosis can be inhibited by dexrazoxane, the iron chelator that is known to prevent clinical development of heart failure at high cumulative anthracycline exposure. Together with clinical evidence for myocyte death after anthracycline exposure, in the form of elevations in serum troponin, make myocyte cell death a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular \'sarcopenia\' characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. Titin is an entropic spring element in the sarcomere that regulates length-dependent calcium sensitivity. Thus titin degradation may lead to impaired diastolic as well as systolic dysfunction, as well as potentiate the effect of suppression of transcription of sarcomere proteins. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. Studies of erbB2 function in viro suggest that signaling through erbB2 by the growth factor neuregulin may regulate cardiac myocyte sarcomere turnover, as well as myocyte-myocyte/myocyte-matrix force coupling. A combination of further in vitro studies, with more careful monitoring of cardiac function after exposure to these cancer therapies, may help to understand to what extent these mechanisms are at work during clinical exposure of the heart to these important pharmaceuticals.


Subject(s)
Anthracyclines/toxicity , Antibiotics, Antineoplastic/toxicity , Heart Diseases/chemically induced , Heart Diseases/pathology , Animals , Antibodies, Monoclonal/toxicity , Antibodies, Monoclonal, Humanized , Cell Death/drug effects , Heart Diseases/metabolism , Humans , Myocytes, Cardiac/drug effects , Sarcomeres/drug effects , Trastuzumab
14.
Exp Cell Res ; 313(8): 1588-601, 2007 May 01.
Article in English | MEDLINE | ID: mdl-17400210

ABSTRACT

Paclitaxel (Taxol) has been successfully combined with the monoclonal antibody trastuzumab (Herceptin) in the treatment of ErbB2 overexpressing cancers. However, this combination therapy showed an unexpected synergistic increase in cardiac dysfunction. We have studied the mechanisms of paclitaxel/anti-ErbB2 cardiotoxicity in adult rat ventricular myocytes (ARVM). Myofibrillar organization was assessed by immunofluorescence microscopy and cell viability was tested by the TUNEL-, LDH- and MTT-assay. Oxidative stress was measured by DCF-fluorescence and myocyte contractile function by video edge-detection and fura-2 fluorescence. Treatment of ARVM with paclitaxel or antibodies to ErbB2 caused a significant increase in myofilament degradation, similarly as observed with an inhibitor of MAPK-signaling, but not apoptosis, necrosis or changes in mitochondrial activity. Paclitaxel-treatment and anti-ErbB2 reduced Erk1/2 phosphorylation. Paclitaxel increased diastolic calcium, shortened relaxation time and reduced fractional shortening in combination with anti-ErbB2. A minor increase in oxidative stress by paclitaxel or anti-ErbB2 was found. We conclude, that concomitant inhibition of ErbB2 receptors and paclitaxel treatment has an additive worsening effect on adult cardiomyocytes, mainly discernible in changes of myofibrillar structure and function, but in the absence of cell death. A potential mechanism is the modulation of the MAPK/Erk1/2 signaling by both drugs.


Subject(s)
Antibodies, Monoclonal/toxicity , Antineoplastic Agents, Phytogenic/toxicity , Glycoproteins/metabolism , Myocytes, Cardiac/drug effects , Paclitaxel/toxicity , Animals , Butadienes/pharmacology , Cell Survival/drug effects , Drug Synergism , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Flavonoids/pharmacology , Glycoproteins/antagonists & inhibitors , Heart Ventricles/cytology , Male , Microtubules/drug effects , Myocardial Contraction , Myocytes, Cardiac/physiology , Myofibrils/drug effects , Nitriles/pharmacology , Phosphorylation , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Receptor, ErbB-2 , Signal Transduction
15.
J Mol Cell Cardiol ; 41(5): 845-54, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17005195

ABSTRACT

Treatment of metastatic breast cancer with doxorubicin (Doxo) in combination with trastuzumab, an antibody targeting the ErbB2 receptor, results in an increased incidence of heart failure. Doxo therapy induces reactive oxygen species (ROS) and alterations of calcium homeostasis. Therefore, we hypothesized that neuregulin-1 beta (NRG), a ligand of the cardiac ErbB receptors, reduces Doxo-induced alterations of EC coupling by triggering antioxidant mechanisms. Adult rat ventricular cardiomyocytes (ARVM) were isolated and treated for 18-48 h. SERCA protein was analyzed by Western blot, EC coupling parameters by fura-2 and video edge detection, gene expression by RT-PCR, and ROS by DCF-fluorescence microscopy. At clinically relevant doses Doxo reduced cardiomyocytes contractility, SERCA protein and SR calcium content. NRG, similarly as the antioxidant N-acetylcystein (NAC), did not affect EC coupling alone, but protected against Doxo-induced damage. NRG and Doxo showed an opposite modulation of glutathione reductase gene expression. NRG, similarly as NAC, reduced peroxide- or Doxo-induced oxidative stress. Specific inhibitors showed, that the antioxidant action of NRG depended on signaling via the ErbB2 receptor and on the Akt- and not on the MAPK-pathway. Therefore, NRG attenuates Doxo-induced alterations of EC coupling and reduces oxidative stress in ARVM. Inhibition of the ErbB2/NRG signaling pathway by trastuzumab in patients concomitantly treated with Doxo might prevent beneficial effects of NRG in the myocardium.


Subject(s)
Doxorubicin/pharmacology , Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Neuregulin-1/pharmacology , Oxidative Stress , Acetylcysteine/pharmacology , Animals , Antibiotics, Antineoplastic/pharmacology , Calcium/metabolism , Doxorubicin/antagonists & inhibitors , Hydrogen Peroxide/pharmacology , Male , Myocytes, Cardiac/physiology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Wistar , Receptor, ErbB-2/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases , Signal Transduction , Ventricular Function
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