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Aimo A, Iborra-Egea O, Martini N, Galvez-Monton C, Burchielli S, Panichella G, Passino C, Emdin M, Bayes-Genis A. Cardiac protection by pirfenidone after myocardial infarction: a bioinformatic analysis. Sci Rep 2022; 12:4691. [PMID: 35304529 PMCID: PMC8933518 DOI: 10.1038/s41598-022-08523-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 02/28/2022] [Indexed: 11/16/2022] Open
Abstract
Left ventricular (LV) remodeling after myocardial infarction (MI) is promoted by an intense fibrotic response, which could be targeted by the anti-fibrotic drug pirfenidone. We explored the relationship between protein modulation by pirfenidone and post-MI remodeling, based on molecular information and transcriptomic data from a swine model of MI. We identified 6 causative motives of post-MI remodeling (cardiomyocyte cell death, impaired myocyte contractility, extracellular matrix remodeling and fibrosis, hypertrophy, renin–angiotensin–aldosterone system activation, and inflammation), 4 pirfenidone targets and 21 bioflags (indirect effectors). Pirfenidone had a more widespread action than gold-standard drugs, encompassing all 6 motives, with prominent effects on p38γ-MAPK12, the TGFβ1-SMAD2/3 pathway and other effector proteins such as matrix metalloproteases 2 and 14, PDGFA/B, and IGF1. A bioinformatic approach allowed to identify several possible mechanisms of action of pirfenidone with beneficial effects in the post-MI LV remodeling, and suggests additional effects over guideline-recommended therapies.
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Affiliation(s)
- Alberto Aimo
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, 56124, Pisa, Italy. .,Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
| | - Oriol Iborra-Egea
- ICREC (Heart Failure and Cardiac Regeneration) Research Programme, Health Sciences Research Institute Germans Trias I Pujol (IGTP), Barcelona, Spain.,CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
| | - Nicola Martini
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Carolina Galvez-Monton
- ICREC (Heart Failure and Cardiac Regeneration) Research Programme, Health Sciences Research Institute Germans Trias I Pujol (IGTP), Barcelona, Spain
| | - Silvia Burchielli
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Giorgia Panichella
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, 56124, Pisa, Italy
| | - Claudio Passino
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, 56124, Pisa, Italy.,Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Michele Emdin
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, 56124, Pisa, Italy.,Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Antoni Bayes-Genis
- ICREC (Heart Failure and Cardiac Regeneration) Research Programme, Health Sciences Research Institute Germans Trias I Pujol (IGTP), Barcelona, Spain.,CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
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Bencsik P, Kiss K, Ágg B, Baán JA, Ágoston G, Varga A, Gömöri K, Mendler L, Faragó N, Zvara Á, Sántha P, Puskás LG, Jancsó G, Ferdinandy P. Sensory Neuropathy Affects Cardiac miRNA Expression Network Targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2 mRNAs. Int J Mol Sci 2019; 20:ijms20040991. [PMID: 30823517 PMCID: PMC6412859 DOI: 10.3390/ijms20040991] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/14/2019] [Accepted: 02/19/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. Results: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.
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Affiliation(s)
- Péter Bencsik
- Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, H-6720 Szeged, Hungary.
- Pharmahungary Group, Graphisoft Park, Záhony utca 7, H-1031 Budapest, Hungary.
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Dóm tér 12, H-6720 Szeged, Hungary.
| | - Krisztina Kiss
- Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, H-6720 Szeged, Hungary.
| | - Bence Ágg
- Pharmahungary Group, Graphisoft Park, Záhony utca 7, H-1031 Budapest, Hungary.
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary.
- Heart and Vascular Center, Semmelweis University, Városmajor utca 68, H-1122 Budapest, Hungary.
| | - Júlia A Baán
- Muscle Adaptation Group, Department of Biochemistry, University of Szeged, Dóm tér 9, H-6720 Szeged, Hungary.
| | - Gergely Ágoston
- Institute of Family Medicine, University of Szeged, Tisza Lajos krt. 109., H-6720 Szeged, Hungary.
| | - Albert Varga
- Institute of Family Medicine, University of Szeged, Tisza Lajos krt. 109., H-6720 Szeged, Hungary.
| | - Kamilla Gömöri
- Pharmahungary Group, Graphisoft Park, Záhony utca 7, H-1031 Budapest, Hungary.
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Dóm tér 12, H-6720 Szeged, Hungary.
| | - Luca Mendler
- Muscle Adaptation Group, Department of Biochemistry, University of Szeged, Dóm tér 9, H-6720 Szeged, Hungary.
- Institute of Biochemistry II, Goethe University Medical School, University Hospital Building 75, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
| | - Nóra Faragó
- Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvári körút 62, H-6726 Szeged, Hungary.
| | - Ágnes Zvara
- Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvári körút 62, H-6726 Szeged, Hungary.
| | - Péter Sántha
- Department of Physiology, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
| | - László G Puskás
- Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvári körút 62, H-6726 Szeged, Hungary.
| | - Gábor Jancsó
- Department of Physiology, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
| | - Péter Ferdinandy
- Pharmahungary Group, Graphisoft Park, Záhony utca 7, H-1031 Budapest, Hungary.
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary.
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IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction. Proc Natl Acad Sci U S A 2016; 113:6949-54. [PMID: 27274047 DOI: 10.1073/pnas.1603127113] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Heart disease is a leading cause of death in adults. Here, we show that a few days after coronary artery ligation and reperfusion, the ischemia-injured heart elaborates the cardioprotective polypeptide, insulin-like growth factor-1 (IGF-1), which activates IGF-1 receptor prosurvival signaling and improves cardiac left ventricular systolic function. However, this signaling is antagonized by the chymase, mouse mast cell protease 4 (MMCP-4), which degrades IGF-1. We found that deletion of the gene encoding MMCP-4 (Mcpt4), markedly reduced late, but not early, infarct size by suppressing IGF-1 degradation and, consequently, diminished cardiac dysfunction and adverse structural remodeling. Our findings represent the first demonstration to our knowledge of tissue IGF-1 regulation through proteolytic degradation and suggest that chymase inhibition may be a viable therapeutic approach to enhance late cardioprotection in postischemic heart disease.
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Milasinovic D, Mohl W. Contemporary perspective on endogenous myocardial regeneration. World J Stem Cells 2015; 7:793-805. [PMID: 26131310 PMCID: PMC4478626 DOI: 10.4252/wjsc.v7.i5.793] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 03/01/2015] [Accepted: 04/20/2015] [Indexed: 02/06/2023] Open
Abstract
Considering the complex nature of the adult heart, it is no wonder that innate regenerative processes, while maintaining adequate cardiac function, fall short in myocardial jeopardy. In spite of these enchaining limitations, cardiac rejuvenation occurs as well as restricted regeneration. In this review, the background as well as potential mechanisms of endogenous myocardial regeneration are summarized. We present and analyze the available evidence in three subsequent steps. First, we examine the experimental research data that provide insights into the mechanisms and origins of the replicating cardiac myocytes, including cell populations referred to as cardiac progenitor cells (i.e., c-kit+ cells). Second, we describe the role of clinical settings such as acute or chronic myocardial ischemia, as initiators of pathways of endogenous myocardial regeneration. Third, the hitherto conducted clinical studies that examined different approaches of initiating endogenous myocardial regeneration in failing human hearts are analyzed. In conclusion, we present the evidence in support of the notion that regaining cardiac function beyond cellular replacement of dysfunctional myocardium via initiation of innate regenerative pathways could create a new perspective and a paradigm change in heart failure therapeutics. Reinitiating cardiac morphogenesis by reintroducing developmental pathways in the adult failing heart might provide a feasible way of tissue regeneration. Based on our hypothesis “embryonic recall”, we present first supporting evidence on regenerative impulses in the myocardium, as induced by developmental processes.
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Peña JR, Pinney JR, Ayala P, Desai TA, Goldspink PH. Localized delivery of mechano-growth factor E-domain peptide via polymeric microstructures improves cardiac function following myocardial infarction. Biomaterials 2015; 46:26-34. [PMID: 25678113 PMCID: PMC4328136 DOI: 10.1016/j.biomaterials.2014.12.050] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 12/09/2014] [Accepted: 12/22/2014] [Indexed: 01/28/2023]
Abstract
The Insulin like growth factor-I isoform mechano-growth factor (MGF), is expressed in the heart following myocardial infarction and encodes a unique E-domain region. To examine E-domain function, we delivered a synthetic peptide corresponding to the unique E-domain region of the human MGF (IGF-1Ec) via peptide eluting polymeric microstructures to the heart. The microstructures were made of poly (ethylene glycol) dimethacrylate hydrogel and bioengineered to be the same size as an adult cardiac myocyte (100 × 15 × 15 μm) and with a stiffness of 20 kPa. Peptide eluting microrods and empty microrods were delivered via intramuscular injection following coronary artery ligation in mice. To examine the physiologic consequences, we assessed the impact of peptide delivery on cardiac function and cardiovascular hemodynamics using pressure-volume loops and gene expression by quantitative RT-PCR. A significant decline in both systolic and diastolic function accompanied by pathologic hypertrophy occurred by 2 weeks which decompensated further by 10 weeks post-infarct in the untreated groups. Delivery of the E-domain peptide eluting microrods decreased mortality, ameliorated the decline in hemodynamics, and delayed decompensation. This was associated with the inhibition of pathologic hypertrophy despite increasing vascular impedance. Delivery of the empty microrods had limited effects on hemodynamics and while pathologic hypertrophy persisted there was a decrease in ventricular stiffness. Our data show that cardiac restricted administration of the MGF E-domain peptide using polymeric microstructures may be used to prevent adverse remodeling of the heart and improve function following myocardial infarction.
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Affiliation(s)
- James R Peña
- Department of Physiology & Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - James R Pinney
- UCSF Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Perla Ayala
- UC Berkeley-UCSF Graduate Group in Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Tejal A Desai
- UC Berkeley-UCSF Graduate Group in Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Paul H Goldspink
- Department of Physiology & Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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Vargas-González A. [Proliferation of adult mammalian ventricular cardiomyocytes: a sporadic but feasible phenomenon]. ARCHIVOS DE CARDIOLOGIA DE MEXICO 2014; 84:102-9. [PMID: 24792902 DOI: 10.1016/j.acmx.2014.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 12/31/2013] [Accepted: 01/06/2014] [Indexed: 11/26/2022] Open
Abstract
Proliferation of adult mammalian ventricular cardiomyocytes has been ruled out by some researchers, who have argued that these cells are terminally differentiated; however, this dogma has been rejected because other researchers have reported that these cells can present the processes necessary to proliferate, that is, DNA synthesis, mitosis and cytokinesis when the heart is damaged experimentally through pharmacological and surgical strategies or due to pathological conditions concerning the cardiovascular system. This review integrates some of the available works in the literature evaluating the DNA synthesis, mitosis and cytokinesis in these myocytes, when the myocardium is damaged, with the purpose of knowing if their proliferation can be considered as a feasible phenomenon. The review is concluded with a reflection about the perspectives of the knowledge generated in this area.
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Affiliation(s)
- Alvaro Vargas-González
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, México, D.F., México.
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The E-domain region of mechano-growth factor inhibits cellular apoptosis and preserves cardiac function during myocardial infarction. Mol Cell Biochem 2013; 381:69-83. [PMID: 23712705 PMCID: PMC3720995 DOI: 10.1007/s11010-013-1689-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 05/16/2013] [Indexed: 11/23/2022]
Abstract
Insulin-like growth factor-1 (IGF-1) isoforms are expressed via alternative splicing. Expression of the minor isoform IGF-1Eb [also known as mechano-growth factor (MGF)] is responsive to cell stress. Since IGF-1 isoforms differ in their E-domain regions, we are interested in determining the biological function of the MGF E-domain. To do so, a synthetic peptide analog was used to gain mechanistic insight into the actions of the E-domain. Treatment of H9c2 cells indicated a rapid cellular uptake mechanism that did not involve IGF-1 receptor activation but resulted in a nuclear localization. Peptide treatment inhibited the intrinsic apoptotic pathway in H9c2 cells subjected to cell stress with sorbitol by preventing the collapse of the mitochondrial membrane potential and inhibition of caspase-3 activation. Therefore, we administered the peptide at the time of myocardial infarction (MI) in mice. At 2 weeks post-MI cardiac function, gene expression and cell death were assayed. A significant decline in both systolic and diastolic function was evident in untreated mice based on PV loop analysis. Delivery of the E-peptide ameliorated the decline in function and resulted in significant preservation of cardiac contractility. Associated with these changes were an inhibition of pathologic hypertrophy and significantly fewer apoptotic nuclei in the viable myocardium of E-peptide-treated mice post-MI. We conclude that administration of the MGF E-domain peptide may provide a means of modulating local tissue IGF-1 autocrine/paracrine actions to preserve cardiac function, prevent cell death, and pathologic remodeling in the heart.
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Obara-Moszynska M, Maceluch J, Bobkowski W, Baszko A, Jaremba O, Krawczynski MR, Niedziela M. A novel mitochondrial DNA deletion in a patient with Kearns-Sayre syndrome: a late-onset of the fatal cardiac conduction deficit and cardiomyopathy accompanying long-term rGH treatment. BMC Pediatr 2013; 13:27. [PMID: 23421922 PMCID: PMC3599412 DOI: 10.1186/1471-2431-13-27] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Accepted: 02/12/2013] [Indexed: 11/16/2022] Open
Abstract
Background Kearns-Sayre Syndrome (KSS) is a multisystem disorder caused by a dysfunction of the oxidative phosphorylation system within mitochondria. Mitochondrial DNA (mtDNA) rearrangements are a key molecular feature of this disease, which manifest a broad phenotypic spectrum. Case presentation Here, we present a boy with KSS whose symptoms included cardiac conduction deficit, cardiomyopathy and growth hormone (GH) deficiency. The patient showed typical symptoms for KSS from early childhood (chronic progressive external ophthalmoplegia, retinopathy, short stature). Long-range PCR analysis disclosed a 7663-base pair heteroplasmic deletion in the mtDNA encompassing nucleotides 6340–14003. At 12 years of age, GH deficiency was recognized and recombinant growth hormone (rGH) therapy was started. At 15 years of age, a complete atrioventicular block was diagnosed and the patient received a pacemaker. During the following 6 months, progressive deterioration of the left ventricle was observed and an echocardiogram showed features of dilated cardiomyopathy. The rGH treatment was then discontinued at a final height of 163 cm. Unfortunately, due to multi-organ insufficiency and inflammation, the patient died at the age of 18 years. Conclusions The response to rGH therapy in the patient was very satisfactory. The large mtDNA deletion had no apparent impact on the response to rGH. Cardiac disturbances occurred as part of the syndrome and were not related to rGH therapy; however, the progression of the disease led to death.
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Affiliation(s)
- Monika Obara-Moszynska
- Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, 27/33 Szpitalna Street, 60-572, Poznan, Poland.
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Abstract
Growth hormone (GH) exerts its effects through insulin-like growth factor-1, and although ubiquitous in human tissues, it has a significant role in cardiovascular function. In recent years, there has been a great deal of interest in GH as an etiologic factor in many cardiovascular disease states. Acromegaly, a state of endogenous GH excess, results in myocardial hypertrophy and decreased cardiac performance with increased cardiovascular mortality. Additional insight into the role of excess GH on the cardiovascular system has been gained from data collected in athletes doping with GH. Likewise, GH deficiency is associated with increased mortality, possibly from the associated increase in atherosclerosis, lipid abnormalities, and endothelial dysfunction. However, further research is required to clarify the benefit of GH treatment in both deficient states and in heart failure patients.
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Sussman MA, Völkers M, Fischer K, Bailey B, Cottage CT, Din S, Gude N, Avitabile D, Alvarez R, Sundararaman B, Quijada P, Mason M, Konstandin MH, Malhowski A, Cheng Z, Khan M, McGregor M. Myocardial AKT: the omnipresent nexus. Physiol Rev 2011; 91:1023-70. [PMID: 21742795 PMCID: PMC3674828 DOI: 10.1152/physrev.00024.2010] [Citation(s) in RCA: 181] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
One of the greatest examples of integrated signal transduction is revealed by examination of effects mediated by AKT kinase in myocardial biology. Positioned at the intersection of multiple afferent and efferent signals, AKT exemplifies a molecular sensing node that coordinates dynamic responses of the cell in literally every aspect of biological responses. The balanced and nuanced nature of homeostatic signaling is particularly essential within the myocardial context, where regulation of survival, energy production, contractility, and response to pathological stress all flow through the nexus of AKT activation or repression. Equally important, the loss of regulated AKT activity is primarily the cause or consequence of pathological conditions leading to remodeling of the heart and eventual decompensation. This review presents an overview compendium of the complex world of myocardial AKT biology gleaned from more than a decade of research. Summarization of the widespread influence that AKT exerts upon myocardial responses leaves no doubt that the participation of AKT in molecular signaling will need to be reckoned with as a seemingly omnipresent regulator of myocardial molecular biological responses.
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Affiliation(s)
- Mark A Sussman
- Department of Biology, San Diego State University, SDSU Heart Institute, San Diego, California 92182, USA.
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Sussman MA. Curiosity killed the cat and found new myocytes. Circ Res 2011; 108:1158-9. [PMID: 21566219 DOI: 10.1161/circresaha.111.245571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Insulin-like growth factor-1 overexpression in cardiomyocytes diminishes ex vivo heart functional recovery after acute ischemia. Cardiovasc Pathol 2011; 21:17-27. [PMID: 21266309 DOI: 10.1016/j.carpath.2010.11.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Revised: 07/29/2010] [Accepted: 11/30/2010] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Acute insulin-like growth factor-1 administration has been shown to have beneficial effects in cardiac pathological conditions. The aim of the present study was to assess the structural and ex vivo functional impacts of long-term cardiomyocyte-specific insulin-like growth factor-1 overexpression in hearts of transgenic αMHC-IGF-1 Ea mice. METHODS Performance of isolated transgenic αMHC-IGF-1 Ea and littermate wild-type control hearts was compared under baseline conditions and in response to 20-min ischemic insult. Cardiac desmin and laminin expression patterns were determined histologically, and myocardial hydroxyproline was measured to assess collagen content. RESULTS Overexpression of insulin-like growth factor-1 did not modify expression patterns of desmin or laminin but was associated with a pronounced increase (∼30%) in cardiac collagen content (from ∼3.7 to 4.8 μg/mg). Baseline myocardial contractile function and coronary flow were unaltered by insulin-like growth factor-1 overexpression. In contrast to prior evidence of acute cardiac protection, insulin-like growth factor-1 overexpression was associated with significant impairment of acute functional response to ischemia-reperfusion. Insulin-like growth factor-1 overexpression did not modify ischemic contracture development, but postischemic diastolic dysfunction was aggravated (51±5 vs. 22±6 mmHg in nontransgenic littermates). Compared with wild-type control, recovery of pressure development and relaxation indices relative to baseline performance were significantly reduced in transgenic αMHC-IGF-1 Ea after 60-min reperfusion (34±7% vs. 62±7% recovery of +dP/dt; 35±11% vs. 57±8% recovery of -dP/dt). CONCLUSIONS Chronic insulin-like growth factor-1 overexpression is associated with reduced functional recovery after acute ischemic insult. Collagen deposition is elevated in transgenic αMHC-IGF-1 Ea hearts, but there is no change in expression of the myocardial structural proteins desmin and laminin. These findings suggest that sustained cardiac elevation of insulin-like growth factor-1 may not be beneficial in the setting of an acute ischemic insult.
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Anversa P, Olivetti G. Cellular Basis of Physiological and Pathological Myocardial Growth. Compr Physiol 2011. [DOI: 10.1002/cphy.cp020102] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Kajstura J, Hosoda T, Bearzi C, Rota M, Maestroni S, Urbanek K, Leri A, Anversa P. The human heart: a self-renewing organ. Clin Transl Sci 2010; 1:80-6. [PMID: 20443822 DOI: 10.1111/j.1752-8062.2008.00030.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The dogma that the heart is a static organ which contains an irreplaceable population of cardiomyocytes prevailed in the cardiovascular field for the last several decades. However, the recent identification of progenitor cells that give rise to differentiated myocytes has prompted a re-interpretation of cardiac biology. The heart cannot be viewed any longer as a postmitotic organ characterized by a predetermined number of myocytes that is defined at birth and is preserved throughout life. The myocardium constitutes a dynamic entity in which new young parenchymal cells are formed to substitute old damaged dying myocytes. The regenerative ability of the heart was initially documented with a classic morphometric approach and more recently with the demonstration that DNA synthesis, mitosis, and cytokinesis take place in the newly formed myocytes of the normal and pathologic heart. Importantly, replicating myocytes correspond to the differentiated progeny of cardiac stem cells. These findings point to the possibility of novel therapeutic strategies for the diseased heart.
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Affiliation(s)
- Jan Kajstura
- Departments of Anesthesia and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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Walsh S, Pontén A, Fleischmann BK, Jovinge S. Cardiomyocyte cell cycle control and growth estimation in vivo--an analysis based on cardiomyocyte nuclei. Cardiovasc Res 2010; 86:365-73. [PMID: 20071355 DOI: 10.1093/cvr/cvq005] [Citation(s) in RCA: 225] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
AIMS Adult mammalian cardiomyocytes are traditionally viewed as being permanently withdrawn from the cell cycle. Whereas some groups have reported none, others have reported extensive mitosis in adult myocardium under steady-state conditions. Recently, a highly specific assay of 14C dating in humans has suggested a continuous generation of cardiomyocytes in the adult, albeit at a very low rate. Mice represent the most commonly used animal model for these studies, but their short lifespan makes them unsuitable for 14C studies. Herein, we investigate the cellular growth pattern for murine cardiomyocyte growth under steady-state conditions, addressed with new analytical and technical strategies, and we furthermore relate this to gene expression patterns. METHODS AND RESULTS The observed levels of DNA synthesis in early life were associated with cardiomyocyte proliferation. Mitosis was prolonged into early life, longer than the most conservative previous estimates. DNA synthesis in neonatal life was attributable to bi-nucleation, therefore suggesting that cardiomyocytes withdraw from the cell cycle shortly after birth. No cell cycle activity was observed in adult cardiomyocytes and significant polyploidy was observed in cardiomyocyte nuclei. CONCLUSION Gene analyses identified 32 genes whose expression was predicted to be particular to day 3-4 neonatal myocytes, compared with embryonic or adult cells. These cell cycle-associated genes are crucial to the understanding of the mechanisms of bi-nucleation and physiological cellular growth in the neonatal period.
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Affiliation(s)
- Stuart Walsh
- Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund SE-22184, Sweden
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Mahmoudabady M, Mathieu M, Touihri K, Hadad I, Da Costa AM, Naeije R, Mc Entee K. Cardiac insulin-like growth factor-1 and cyclins gene expression in canine models of ischemic or overpacing cardiomyopathy. BMC Cardiovasc Disord 2009; 9:49. [PMID: 19818143 PMCID: PMC2763849 DOI: 10.1186/1471-2261-9-49] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2009] [Accepted: 10/09/2009] [Indexed: 01/18/2023] Open
Abstract
Background Insulin-like growth factor-1 (IGF-1), transforming growth factor β (TGFβ) and cyclins are thought to play a role in myocardial hypertrophic response to insults. We investigated these signaling pathways in canine models of ischemic or overpacing-induced cardiomyopathy. Methods Echocardiographic recordings and myocardial sampling for measurements of gene expressions of IGF-1, its receptor (IGF-1R), TGFβ and of cyclins A, B, D1, D2, D3 and E, were obtained in 8 dogs with a healed myocardial infarction, 8 dogs after 7 weeks of overpacing and in 7 healthy control dogs. Results Ischemic cardiomyopathy was characterized by moderate left ventricular systolic dysfunction and eccentric hypertrophy, with increased expressions of IGF-1, IGF-1R and cyclins B, D1, D3 and E. Tachycardiomyopathy was characterized by severe left ventricular systolic dysfunction and dilation with no identifiable hypertrophic response. In the latter model, only IGF-1 was overexpressed while IGF-1R, cyclins B, D1, D3 and E stayed unchanged as compared to controls. The expressions of TGFβ, cyclins A and D2 were comparable in the 3 groups. The expression of IGF-1R was correlated with the thickness of the interventricular septum, in systole and diastole, and to cyclins B, D1, D3 and E expression. Conclusion These results agree with the notion that IGF-1/IGF-1R and cyclins are involved in the hypertrophic response observed in cardiomyopathies.
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Affiliation(s)
- Maryam Mahmoudabady
- Laboratory of Physiology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
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17
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Pucci A, Zanini C, Granata R, Ghignone R, Iavarone A, Broglio F, Sorrentino P, Bergamasco L, Rinaldi M, Ghigo E. Myocardial insulin-like growth factor-1 and insulin-like growth factor binding protein-3 gene expression in failing hearts harvested from patients undergoing cardiac transplantation. J Heart Lung Transplant 2009; 28:402-5. [PMID: 19332270 DOI: 10.1016/j.healun.2008.12.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2008] [Revised: 11/14/2008] [Accepted: 12/29/2008] [Indexed: 10/21/2022] Open
Abstract
Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding proteins (IGFBPs) might play a pathogenic role in heart failure. We showed significantly increased myocardial IGFBP-3 expression (investigated by real-time polymerase chain reaction) and apoptosis (detected by flow cytometry) in 23 failing hearts from patients undergoing cardiac transplantation for end-stage dilated or ischemic cardiomyopathy, when compared with 10 controls. Higher IGF-1 mRNA levels were shown only in end-stage dilated cardiomyopathy.
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Affiliation(s)
- Angela Pucci
- Department of Pathology, Regina Margherita Hospital, Torino, Italy.
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18
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Stavropoulou A, Halapas A, Sourla A, Philippou A, Papageorgiou E, Papalois A, Koutsilieris M. IGF-1 expression in infarcted myocardium and MGF E peptide actions in rat cardiomyocytes in vitro. Mol Med 2009; 15:127-35. [PMID: 19295919 DOI: 10.2119/molmed.2009.00012] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2009] [Accepted: 03/05/2009] [Indexed: 11/06/2022] Open
Abstract
Insulinlike growth factor-1 (IGF-1) expression is implicated in myocardial pathophysiology, and two IGF-1 mRNA splice variants have been detected in rodents, IGF-1Ea and mechano-growth factor (MGF). We investigated the expression pattern of IGF-1 gene transcripts in rat myocardium from 1 h up to 8 wks after myocardial infarction induced by left anterior descending coronary artery ligation. In addition, we characterized IGF-1 and MGF E peptide action and their respective signaling in H9C2 myocardial-like cells in vitro. IGF-1Ea and MGF expression were significantly increased, both at transcriptional and translational levels, during the late postinfarction period (4 and 8 wks) in infarcted rat myocardium. Measurements of serum IGF-1 levels in infarcted rats were initially decreased (24 h up to 1 wk) but remained unaltered throughout the late experimental phase (4 to 8 wks) compared with sham-operated rats. Furthermore, specific anti-IGF-1R neutralizing antibody failed to block the synthetic MGF E peptide action, whereas it completely blocked IGF-1 action on the proliferation of H9C2 cells. Moreover, this synthetic MGF E peptide did not activate Akt phosphorylation, whereas it activated ERK1/2 in H9C2 rat myocardial cells. These data support the role of IGF-1 expression in the myocardial repair process and suggest that synthetic MGF E peptide actions may be mediated via an IGF-1R independent pathway in rat myocardial cells, as suggested by our in vitro experiments.
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Affiliation(s)
- Anastasia Stavropoulou
- Department of Experimental Physiology, Medical School, National Kapodistrian University of Athens, Goudi-Athens, Greece
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19
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Mattson MP, Wan R. Neurotrophic factors in autonomic nervous system plasticity and dysfunction. Neuromolecular Med 2008; 10:157-68. [PMID: 18172785 DOI: 10.1007/s12017-007-8021-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2007] [Accepted: 11/20/2007] [Indexed: 01/26/2023]
Abstract
During development, neurotrophic factors are known to play important roles in regulating the survival of neurons in the autonomic nervous system (ANS) and the formation of their synaptic connectivity with their peripheral targets in the cardiovascular, digestive, and other organ systems. Emerging findings suggest that neurotrophic factors may also affect the functionality of the ANS during adult life and may, in part, mediate the effects of environmental factors such as exercise and dietary energy intake on ANS neurons and target cells. In this article, we describe the evidence that ANS neurons express receptors for multiple neurotrophic factors, and data suggesting that activation of those receptors can modify plasticity in the ANS. Neurotrophic factors that may regulate ANS function include brain-derived neurotrophic factor, nerve growth factor, insulin-like growth factors, and ciliary neurotrophic factor. The possibility that perturbed neurotrophic factor signaling is involved in the pathogenesis of ANS dysfunction in some neurological disorders is considered, together with implications for neurotrophic factor-based therapeutic interventions.
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Affiliation(s)
- Mark P Mattson
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD. USA.
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20
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Matsui T, Nagoshi T, Hong EG, Luptak I, Hartil K, Li L, Gorovits N, Charron MJ, Kim JK, Tian R, Rosenzweig A. Effects of chronic Akt activation on glucose uptake in the heart. Am J Physiol Endocrinol Metab 2006; 290:E789-97. [PMID: 16352665 DOI: 10.1152/ajpendo.00564.2004] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Acute activation of the serine-threonine kinase Akt is cardioprotective and increases glucose uptake, at least in part, through enhanced expression of GLUT4 on the sarcolemma. The effects of chronic Akt activation on glucose uptake in the heart remain unclear. To address this issue, we examined the effects of chronic Akt activation on glucose uptake, glycogen storage, and relevant glucose transporters in the hearts of transgenic mice. We found that chronic cardiac activation of Akt led to a substantial increase in the rate of basal glucose uptake (P < 0.05) but blunted the response to insulin (1.9 vs. 18.1-fold increase compared with baseline) using NMR in ex vivo perfused heart. Basal glucose uptake was also increased in Akt transgenic mice in vivo (P < 0.005). These changes were associated with an increase on glycogen deposition, examined with histochemical staining, biochemical (>6-fold, P < 0.001) and in vivo radioactive (5-fold, P < 0.01) assays. Studies in chimeric hearts of female X-linked transgenic Akt mice suggested that increased glycogen deposition occurred as a cell autonomous effect of transgene expression. Interestingly, although sarcolemmal GLUT1 was not significantly altered, chronic Akt activation actually decreased plasma membrane GLUT4. Moreover, intracellular pools of GLUT1 were modestly reduced, whereas intracellular GLUT4 was substantially reduced. It seems likely that neither GLUT1 nor GLUT4 explains the increase in basal glucose uptake but that these reductions contribute to the loss of insulin responsiveness that we observed. These data demonstrate that chronic Akt activation increases basal glucose uptake and glycogen deposition while inhibiting the response to insulin.
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Affiliation(s)
- Takashi Matsui
- Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
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21
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Bettiol E, Clement S, Krause KH, Jaconi ME. Embryonic and adult stem cell-derived cardiomyocytes: lessons from in vitro models. Rev Physiol Biochem Pharmacol 2006; 157:1-30. [PMID: 17236648 DOI: 10.1007/112_0508] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
For years, research has focused on how to treat heart failure by sustaining the overloaded remaining cardiomyocytes. Recently, the concept of cell replacement therapy as a treatment of heart diseases has opened a new area of investigation. In vitro-generated cardiomyocytes could be injected into the heart to rescue the function of a damaged myocardium. Embryonic and/or adult stem cells could provide cardiac cells for this purpose. Knowledge of fundamental cardiac differentiation mechanisms unraveled by studies on animal models has been improved using in vitro models of cardiogenesis such as mouse embryonal carcinoma cells, mouse embryonic stem cells and, recently, human embryonic stem cells. On the other hand, studies suggesting the existence of cardiac stem cells and the potential of adult stem cells from bone marrow or skeletal muscle to differentiate toward unexpected phenotypes raise hope and questions about their potential use for cardiac cell therapy. In this review, we compare the specificities of embryonic vs adult stem cell populations regarding their cardiac differentiation potential, and we give an overview of what in vitro models have taught us about cardiogenesis.
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Affiliation(s)
- E Bettiol
- University of Geneva, Department of Pathology and Immunology, Faculty of Medicine, Switzerland
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22
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Palmen M, Twickler MT, Daemen MJ, Cramer MJ, Doevendans PA. The role of insulin-like growth factor during a postischemic period - new insights into pathophysiologic pathways in cardiac tissue. Future Cardiol 2005; 1:479-88. [PMID: 19804148 DOI: 10.2217/14796678.1.4.479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Despite an improvement in the therapeutic strategies available for an acute ischemic event, cardiac disease is still the principal cause of morbidity and mortality in Western societies. A shift from acute towards more chronic heart disease due to atherosclerotic disease has been recognized. Modification of adaptive capacities of the cardiac muscle after damage remains a key component in the prevention of chronic cardiac disease, such as overt heart failure. It has recently been demonstrated that local insulin-like growth factor (IGF)-1 homeostasis in the cardiac tissue is closely involved in postischemic adaptation, such as the process of remodeling. Both experimental and clinical data support the theory that IGF-1 plays a key role in the adaptive response of the myocardium during both acute myocardial ischemia and chronic myocardial failure, regulating left ventricular remodeling and thereby restoring left ventricular architecture. This eventually leads to improvement in the function of the failing heart. While most experimental data support the beneficial role of IGF-1 in restoring architecture and function of the failing heart, clinical trials investigating the role of IGF-1 treatment of patients in cardiac failure show conflicting results. In this bench-to-bedside review, the authors aim to highlight recent advances in knowledge of the role of paracrine and autocrine IGF balances during postischemic cardiac adaptation, in order to present possible new initiatives concerning therapeutic strategies in maladaptive cardiac performance, such as the syndrome of heart failure.
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Affiliation(s)
- Meindert Palmen
- Department of Cardiothoracic Surgery, CARIM, AZM Maastricht, The Netherlands
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23
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Matthews KG, Devlin GP, Stuart SP, Jensen JA, Doughty RN, Conaglen JV, Bass JJ. Intrapericardial IGF-I Improves Cardiac Function in an Ovine Model of Chronic Heart Failure. Heart Lung Circ 2005; 14:98-103. [PMID: 16352263 DOI: 10.1016/j.hlc.2005.02.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2004] [Revised: 01/16/2005] [Accepted: 02/22/2005] [Indexed: 11/22/2022]
Abstract
BACKGROUND Following myocardial infarction, progressive deterioration of left ventricular function often follows, leading eventually to overt heart failure. In the myocardium, there is increased expression of insulin-like growth factor I (IGF-I) mRNA, protein and receptor levels, particularly in the peri-infarct zone, suggesting that IGF-I has a role to play in post-infarct cardiac structure and function. In this study, we examine the effects of exogenous IGF-I on cardiac function. METHODS Intrapericardial IGF-I (15 microg/kg/d, n=3) or vehicle (sterile saline, n=3) was administered to sheep in chronic heart failure and the results of intrapericardial delivery compared with those of subcutaneous delivery. Left ventricular ejection fraction (EF) was measured to assess cardiac performance. Concentrations of plasma IGF-I were quantified by radioimmunoassay. RESULTS Intrapericardial delivery of IGF-I resulted in a rapid and sustained increase (P<0.001) in EF, which remained elevated 14 days after cessation of treatment. Subcutaneous IGF-I treatment did not affect EF. Both subcutaneous and intrapericardial IGF-I administration increased concentrations of plasma IGF-I, although concentrations declined prior to the cessation of treatment. CONCLUSIONS We conclude that the higher concentration of IGF-I in the myocardium, which results from intrapericardial delivery significantly increases EF in chronic heart failure but that subcutaneous delivery of IGF-I does not.
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Affiliation(s)
- Kenneth G Matthews
- Functional Muscle Genomics Group, AgResearch Ruakura, East Street, Hamilton, New Zealand.
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24
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Wang TL, Huang YH, Chang H. Somatostatin Analogue Mimics Acute Ischemic Preconditioning in a Rat Model of Myocardial Infarction. J Cardiovasc Pharmacol 2005; 45:327-32. [PMID: 15772521 DOI: 10.1097/01.fjc.0000156823.35210.21] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
We tested the hypothesis that octreotide, a somatostatin analogue, can mimic ischemic preconditioning (PC) to provide cardioprotection against myocardial infarction. An ischemia-reperfusion model of adult Wistar rats was used. Infarct size was expressed as a percentage of the area at risk under different treatment protocols. Octreotide PC (35 microg/Kg 20 minutes before ischemia-reperfusion) significantly decreased infarct size (18 +/- 4%) versus control (60 +/- 7%). The somatostatin receptor antagonist cyclo-somatostatin (0.5 mg/Kg) could blunt the above cardioprotection. Administration of either chelerythrine (a protein kinase C inhibitor, 2 mg/Kg) or genistein (a tyrosine kinase inhibitor, 5 mg/Kg) could also block octreotide PC (54 +/- 7% and 58 +/- 6%, respectively). Pretreatment with the mitochondrial ATP-sensitive potassium channel antagonist 5-hydroxydecanoic acid (5-HD) and the sarcolemmal ATP-sensitive potassium channel antagonist glibenclamide could abolish the effects of octreotide PC (54 +/- 6% and 52 +/- 6%). Chelerythrine, however, had no effect on octreotide PC. In conclusion, the present study demonstrates that octreotide can mimic ischemic PC to reduce infarct size. Acute effects of octreotide PC involve the activation of protein kinase C, tyrosine kinase C, and mitochondrial ATP-sensitive potassium channels, but not systemic IGF-I activation.
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Affiliation(s)
- Tzong-Luen Wang
- Department of Emergency Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
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25
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Metzger M, Higuchi ML, Moreira LF, Chaves MJF, Castelli JB, Silvestre JML, Bocchi E, Stolf N, Ramires JA. Relevance of apoptosis and cell proliferation for survival of patients with dilated cardiomyopathy undergoing partial left ventriculectomy. Eur J Clin Invest 2002; 32:394-9. [PMID: 12059983 DOI: 10.1046/j.1365-2362.2002.00998.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Cardiomyocyte apoptosis as well as proliferation have been described in congestive heart failure, but their clinical relevance remains unclear. In order to clarify whether apoptosis and cell proliferation occur in patients with idiopathic dilated cardiomyopathy and whether their degree in left ventricle fragments resected during partial left ventriculectomy has any influence on the outcome after this surgery, we compared their occurrence in four groups of patients: group A, short-term survivors (n = 18); group B, deaths within 6 months of the surgery (n = 13); group C, long-term survivors (n = 12); and Group D, deaths within 60 months (n = 19). DESIGN Apoptotic cardiomyocytes and interstitial cells were quantified in left ventricle fragments from 31 patients with idiopathic-dilated cardiomyopathy using the TUNEL assay. Cell proliferation was quantified in parallel sections by KI-67 immunohistochemistry. RESULTS Apoptotic cells were present in the majority of cases (n = 24) and proliferative cells in all cases. Whereas there was no significant difference regarding all parameters examined between Groups A and B, there was a highly significant difference between Groups C and D in the number of apoptotic cardiomyocytes (P = 0.012) and apoptotic interstitial cells (P = 0.006). There was no significant relationship between apoptotic cardiomyocytes and KI-67-positive cardiomyocytes, but a negative correlation between apoptotic interstitial cells and KI-67-positive interstitial cells (r = -0.383; P = 0.028). CONCLUSION Cardiomyocyte apoptosis and proliferation occur in the majority of patients with idiopathic-dilated cardiomyopathy. High numbers of apoptotic cardiomyocytes and apoptotic interstitial cells are significantly related to a bad late outcome after partial left ventriculectomy.
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Affiliation(s)
- M Metzger
- Heart Institute (InCor), University of São Paulo Medical School, Brazil.
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26
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Welch S, Plank D, Witt S, Glascock B, Schaefer E, Chimenti S, Andreoli AM, Limana F, Leri A, Kajstura J, Anversa P, Sussman MA. Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. Circ Res 2002; 90:641-8. [PMID: 11934830 DOI: 10.1161/01.res.0000013780.77774.75] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
To test the hypothesis that early interventional treatment with insulin-like growth factor-1 (IGF-1) alleviates subsequent development of dilated cardiomyopathy, cardiac-specific IGF-1 expression was introduced by selective cross-breeding into a transgenic mouse model of heart failure that displays phenotypic characteristics of severe dilation. Hemodynamic, structural, and cellular parameters of the heart were compared between nontransgenic, tropomodulin-overexpressing cardiomyopathic, and the hybrid tropomodulin/IGF-1-overexpressing mice. Beneficial effects of IGF-1 were apparent by multiple indices of cardiac structure and function, including normalization of heart mass, anatomy, hemodynamics, and apoptosis. IGF-1 expression also acted as a proliferative stimulus as evidenced by calculated increases in myocyte number as well as expression of Ki67, a nuclear marker of cellular replication. Cellular analyses revealed that IGF-1 inhibited characteristic cardiomyocyte elongation in dilated hearts and restored calcium dynamics comparable to that observed in normal cells. Collectively, these results provide novel information regarding the ability of IGF-1 to inhibit progression of cardiomyopathic disease in a defined model system and suggest that heart failure may benefit from early interventional IGF-1 treatment.
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Affiliation(s)
- Sara Welch
- Divisions of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, USA
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27
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Huang CY, Hao LY, Buetow DE. Hypertrophy of cultured adult rat ventricular cardiomyocytes induced by antibodies against the insulin-like growth factor (IGF)-I or the IGF-I receptor is IGF-II-dependent. Mol Cell Biochem 2002; 233:65-72. [PMID: 12083381 DOI: 10.1023/a:1015514324328] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Antibodies against the insulin-like growth factor-I (IGF-I) or the IGF-I receptor (IGF-IR) directly initiate a rapid (within 6 h) hypertrophy of isolated adult rat ventricular cardiomyocytes cultured in the absence of serum. Further, cardiomyocytes treated with either of these agonistic antibodies upregulate the expression of their genes for insulin-like growth factor-II (IGF-II) and the IGF-II receptor (IGF-IIR). Genistein, an inhibitor of the tyrosine kinase IGF-IR, also induces the cardiomyocytes to hypertrophy. Anti-IGF-II antibody inhibits the cardiomyocyte hypertrophy induced by anti-IGF-I and anti-IGF-IR antibodies or by genistein. Results are consistent with a model in which local production of IGF-II is upregulated when the IGF-IR signaling pathway is blocked and in which an IGF-II-mediated pathway, likely involving the IGF-IIR, then stimulates hypertrophy of the cardiomyocytes.
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Affiliation(s)
- Chih-Yang Huang
- Department of Molecular and Integrative Physiology, University of Illinois, Urbana 61801, USA
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28
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Abstract
Introduced several decades ago, the dogma persists that ventricular myocytes are terminally differentiated cells and cardiac repair by myocyte regeneration is completely inhibited shortly after birth. On the basis that cardiac myocytes are unable to divide in the adult heart, myocyte growth under physiologic and pathologic conditions is believed to be restricted to cellular hypertrophy. Evidence is presented to indicate that this old paradigm has to be changed to include myocyte replication as a significant component of the cellular processes of ventricular remodeling. Importantly, myocyte death, apoptotic and necrotic in nature, has to be regarded as an additional critical variable of the multifactorial events implicated in the alterations of cardiac anatomy and myocardial structure of the decompensated heart. Methodologies are currently available to recognize and measure quantitatively the contribution of myocyte size, number and death to the adaptation of the overloaded heart and its progression to cardiac failure.
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Affiliation(s)
- Piero Anversa
- Cardiovascular Research Institute, Department of Medicine, Valhalla, New York 10595, USA.
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29
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Al-Obaidi MK, Hon JK, Stubbs PJ, Barnes J, Amersey RA, Dahdal M, Laycock JF, Noble MI, Alaghband-Zadeh J. Plasma insulin-like growth factor-1 elevated in mild-to-moderate but not severe heart failure. Am Heart J 2001; 142:E10. [PMID: 11717621 DOI: 10.1067/mhj.2001.118116] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Insulin-like growth factor 1 (IGF-1) promotes favorable cardiac remodeling in heart failure. However, the relation of plasma IGF-1 in patients with various degrees of heart failure is not known. METHODS Venous plasma samples were collected from patients with clinically documented heart failure (n = 24) and from control subjects (n = 21) for measurements of IGF-1 levels. In the heart failure group, functional assessment of the physical capacity was determined by means of the New York Heart Association (NYHA) score. Objective determination of ventricular performance was made by transthoracic echocardiographic measurement of left ventricular fractional shortening (FS). RESULTS IGF-1 levels were higher in patients with heart failure (mean age, 67 +/- 2 years; 17 men) than in control subjects (age, 71 +/- 2 years; 9 men) (20.2 +/- 2 mU/L, 14.1 +/- 2 mU/L, respectively, P <.05). However, the elevated IGF-1 levels were demonstrated only in patients with mild-to-moderate symptoms (NYHA classes I and II) of heart failure (24.7 +/- 3.3 mU/L, n = 12, P =.005 vs control subjects) but not in patients with severe symptoms (NYHA classes III and IV) (15.7 +/- 2.3 mU/L, n = 12). There was a strong positive correlation between IGF-1 levels and left ventricular FS (%) (r = 0.58, P =.003, n = 24). Adjustments for other potential confounders including age, sex, treatment received, and underlying cause of heart failure did not alter the relation between IGF-1 and left ventricular FS (odds ratio, 2.01; 95% confidence interval, 1.26 to 6.24; P =.01). CONCLUSIONS Plasma levels of IGF-1 show distinct variations with the severity of heart failure and may play a vital role in compensated heart failure.
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Affiliation(s)
- M K Al-Obaidi
- National Heart and Lung Institute, Department of Cardiology, Imperial College School of Medicine, London, UK.
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30
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De Windt LJ, Lim HW, Taigen T, Wencker D, Condorelli G, Dorn GW, Kitsis RN, Molkentin JD. Calcineurin-mediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo: An apoptosis-independent model of dilated heart failure. Circ Res 2000; 86:255-63. [PMID: 10679475 DOI: 10.1161/01.res.86.3.255] [Citation(s) in RCA: 160] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We have previously shown that the calcium-calmodulin-regulated phosphatase calcineurin (PP2B) is sufficient to induce cardiac hypertrophy that transitions to heart failure in transgenic mice. Given the rapid onset of heart failure in these mice, we hypothesized that calcineurin signaling would stimulate myocardial cell apoptosis. However, utilizing multiple approaches, we determined that calcineurin-mediated hypertrophy protected cardiac myocytes from apoptosis, suggesting a model of heart failure that is independent of apoptosis. Adenovirally mediated gene transfer of a constitutively active calcineurin cDNA (AdCnA) was performed in cultured neonatal rat cardiomyocytes to elucidate the mechanism whereby calcineurin affected myocardial cell viability. AdCnA infection, which induced myocyte hypertrophy and atrial natriuretic factor expression, protected against apoptosis induced by 2-deoxyglucose or staurosporine, as assessed by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) labeling, caspase-3 activation, DNA laddering, and cellular morphology. The level of protection conferred by AdCnA was similar to that of adenoviral Bcl-x(L) gene transfer or hypertrophy induced by phenylephrine. In vivo, failing hearts from calcineurin-transgenic mice did not demonstrate increased TUNEL labeling and, in fact, demonstrated a resistance to ischemia/reperfusion-induced apoptosis. We determined that the mechanism whereby calcineurin afforded protection from apoptosis was partially mediated by nuclear factor of activated T cells (NFAT3) signaling and partially by Akt/protein kinase B (PKB) signaling. Although calcineurin activation protected myocytes from apoptosis, inhibition of calcineurin with cyclosporine was not sufficient to induce TUNEL labeling in Gqalpha-transgenic mice or in cultured cardiomyocytes. Collectively, these data identify a calcineurin-dependent mouse model of dilated heart failure that is independent of apoptosis.
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Affiliation(s)
- L J De Windt
- Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA
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31
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Leroith D, Blakesley VA, Werner H. Molecular Mechanisms of Insulin‐like Growth Factor I Receptor Function: Implications for Normal Physiology and Pathological States. Compr Physiol 1999. [DOI: 10.1002/cphy.cp070520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Takahashi T, Fukuda K, Pan J, Kodama H, Sano M, Makino S, Kato T, Manabe T, Ogawa S. Characterization of insulin-like growth factor-1-induced activation of the JAK/STAT pathway in rat cardiomyocytes. Circ Res 1999; 85:884-91. [PMID: 10559134 DOI: 10.1161/01.res.85.10.884] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
This study was designed to investigate whether insulin-like growth factor-1 (IGF-1) transduces signaling through the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and to assess the upstream signals of serine and tyrosine phosphorylation of STAT family proteins. Primary cultured neonatal rat cardiomyocytes were stimulated with IGF-1 (10(-8) mol/L). JAK1, but not JAK2 or Tyk2, was phosphorylated by IGF-1 as early as 2 minutes and peaked at 5 minutes. IGF-1 induced both tyrosine and serine phosphorylation of STAT1 and STAT3. Tyrosine phosphorylation of STAT1 peaked at 15 minutes and correlated with that of JAK1, whereas that of STAT3 was sustained up to 120 minutes and was dissociated from the activation of JAK1. Tyrosine phosphorylation of STAT3 was unaffected by the preincubation with CV11974 (AT(1) blocker), TAK044 (endothelin-1 receptor blocker), RX435 (anti-gp130 blocking antibody), PD98058, wortmannin, EDTA, or KN62 but was significantly attenuated by BAPTA-AM and chelerythrine. The time course of a gel mobility shift of SIE (sis-inducing element) coincided with the phosphorylation of STAT3. Serine phosphorylation of STAT1 peaked at 30 minutes and that of STAT3 was observed from 5 to 60 minutes. These results indicated that (1) IGF-1 activated JAK1 but not JAK2 or Tyk2 in rat cardiomyocytes; (2) IGF-1 induced both tyrosine and serine phosphorylation of STAT1 and STAT3; and (3) the tyrosine phosphorylation of STAT3 was not caused by JAK1 alone, and protein kinase C and intracellular Ca(2+) were required for phosphorylation.
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Affiliation(s)
- T Takahashi
- Cardiopulmonary Division, Department of Internal Medicine, Keio University, Tokyo, Japan
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Delaughter MC, Taffet GE, Fiorotto ML, Entman ML, Schwartz RJ. Local insulin-like growth factor I expression induces physiologic, then pathologic, cardiac hypertrophy in transgenic mice. FASEB J 1999; 13:1923-9. [PMID: 10544175 DOI: 10.1096/fasebj.13.14.1923] [Citation(s) in RCA: 115] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
In the present study we determined the long-term effects of persistent, local insulin-like growth factor I (IGF-I) expression on cardiac function in the SIS2 transgenic mouse. Cardiac mass/tibial length was increased in SIS2 mice by 10 wk of age; this cardiac hypertrophy became more pronounced later in life. Peak aortic outflow velocity, a correlate of cardiac output, was increased at 10 wk in SIS2 mice but was decreased at 52 wk. 72 wk SIS2 mouse hearts exhibited wide variability in the extent of cardiac hypertrophy and enlargement of individual cardiac myofibers. Sirius red staining revealed increased fibrosis in 72 wk SIS2 hearts. Persistent local IGF-I expression is sufficient to initially induce an analog of physiological cardiac hypertrophy in which peak aortic outflow velocity is increased relative to controls in the absence of any observed detrimental histological changes. However, this hypertrophy progresses to a pathological condition characterized by decreased systolic performance and increased fibrosis. Our results confirm the short-term systolic performance benefit of increased IGF-I, but our demonstration that IGF-I ultimately diminishes systolic performance raises doubt about the therapeutic value of chronic IGF-I administration. Considering these findings, limiting temporal exposure to IGF-I seems the most likely means of delivering IGF-I's potential benefits while avoiding its deleterious side effects.
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Affiliation(s)
- M C Delaughter
- Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA
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Leri A, Liu Y, Wang X, Kajstura J, Malhotra A, Meggs LG, Anversa P. Overexpression of insulin-like growth factor-1 attenuates the myocyte renin-angiotensin system in transgenic mice. Circ Res 1999; 84:752-62. [PMID: 10205143 DOI: 10.1161/01.res.84.7.752] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Constitutive overexpression of insulin-like growth factor-1 (IGF-1) in myocytes protects them from apoptosis and interferes with myocyte hypertrophy in the normal and pathological heart. Conversely, angiotensin II (Ang II) triggers cell death and promotes myocyte hypertrophy. Moreover, activation of p53 upregulates the cellular renin-angiotensin system (RAS). Therefore, IGF-1 overexpression in FVB.Igf+/- mice may downregulate the local RAS through the attenuation of p53 and p53-inducible genes. On this basis, p53 DNA binding activity to angiotensinogen (Aogen), bax, and the AT1 receptor was determined in left ventricular myocytes from FVB.Igf-/- and FVB.Igf+/- mice. The quantity of Bax, Bcl-2, Aogen, and AT1 receptor in these cells was evaluated. The presence of Mdm2-p53 complexes was also established. Finally, Ang II levels in myocytes were measured. Upregulation of IGF-1 in myocytes was associated with a protein-to-protein interaction between Mdm2 and p53, which attenuated p53 transcriptional activity for bax, Aogen, and AT1 receptor. Similarly, the amount of Bax, Aogen, and AT1 receptor proteins in these cells decreased. In contrast, the expression of Bcl-2 remained constant. The downregulation of Aogen in myocytes from FVB.Igf+/- mice was characterized by a reduction in Ang II. In conclusion, IGF-1 negatively influences the myocyte RAS through the upregulation of Mdm2 and its binding to p53. This may represent the molecular mechanism responsible for the effects of IGF-1 on cell viability and myocyte hypertrophy in the nonpathological and pathological heart in vivo.
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Affiliation(s)
- A Leri
- Department of Medicine, New York Medical College, Valhalla, NY, USA
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35
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Borisov AB. Regeneration of skeletal and cardiac muscle in mammals: do nonprimate models resemble human pathology? Wound Repair Regen 1999; 7:26-35. [PMID: 10231503 DOI: 10.1046/j.1524-475x.1999.00026.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Most of the available information regarding the regenerative potential and compensatory remodeling of mammalian tissues has been obtained from nonprimate animals, mainly rodent experimental models. The increasing use of transgenic mice for studies of the mechanisms controlling organogenesis and regeneration also requires a clear understanding of their applicability as experimental models for studies of similar processes in humans and other mammals. Application of modern cell biology methods to studies of regenerative processes has provided new insights into similarity and differences in cellular responses to injury in the tissues of different mammalian species. During more than 200-million years of progressive divergent evolution of mammals, cellular mechanisms of tissue regeneration and compensatory remodeling evolved together with increasingly adaptive functional specialization and structural complexity of mammalian tissues and organs. Rodents represent a phylogenetically ancient order of mammals that has conservatively retained a number of morphofunctional characteristics of early representatives of this class, which include enhanced regenerative capacity of tissues. A comparative analysis of regenerative processes in skeletal and cardiac muscle, as well as in several other mammalian tissues, shows that time courses and intensities of regeneration in response to the same type of injury vary even within taxonomically related species (e.g., rat, mouse, and hamster). The warm bloodedness of mammals facilitated the development of more complex mechanisms of metabolic, immune, and neurohumoral regulation, which resulted in a stronger dependence of regenerative processes on vascularization and innervation. For this reason, interspecies modifications of regenerative responses are limited by the capacity of the animal to resorb rapidly the foci of necrosis and to revascularize and reinnervate the volume of the regenerating tissue. These differences, among other factors, result in significantly lower rates of reparative regeneration in mammals possessing larger body sizes than rodents. A review of these data strongly indicates that the phylogenetic age and biological differences between different species should be taken into account before extrapolation of regenerative properties of nonprimate tissues on the regenerative responses in the primates.
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Affiliation(s)
- A B Borisov
- Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, Mich. 48109-0616, USA
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Affiliation(s)
- P Anversa
- Department of Medicine, New York Medical College, Valhalla 10595, USA
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Reiss K, Cheng W, Pierzchalski P, Kodali S, Li B, Wang S, Liu Y, Anversa P. Insulin-like growth factor-1 receptor and its ligand regulate the reentry of adult ventricular myocytes into the cell cycle. Exp Cell Res 1997; 235:198-209. [PMID: 9281369 DOI: 10.1006/excr.1997.3669] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
To determine whether insulin-like growth factor-1 (IGF-1) stimulation in vitro of ventricular myocytes isolated from infarcted hearts is characterized by the reentry of cells into the cell cycle, the expression and kinase activity of cyclins E, A, and B and DNA synthesis were evaluated 5 days after coronary artery occlusion and 24 and 48 h following the addition of IGF-1. Myocytes surviving an acute myocardial infarction were employed because of their increase in surface insulin-like growth factor-1 receptors (IGF-1R). Western blot analysis documented that IGF-1 resulted in an upregulation of cyclins D1, E, A, and B in viable postinfarcted myocytes. Cyclin E- and A-associated histone H1 kinase activity and cyclin D1-associated retinoblastoma protein-associated kinase activity also increased, but cyclin B kinase activity was not enhanced by IGF-1. These changes in cyclins and kinase activities were characterized by a significant increase in the number of cells labeled by bromodeoxyuridine, from approximately 630/10(6) to nearly 9, 000/10(6) myocytes. This latter value was reduced by more than 50% by antisense oligodeoxynucleotide to IGF-1R mRNA. However, IGF-1 stimulation did not induce nuclear mitotic division and cytokinesis. In conclusion, the growth-promoting effect of IGF-1 on adult myocytes is regulated by the density of IGF-1R, which conditions the activation of the replicatory machinery of the cells. The failure of IGF-1 to enhance cyclin B kinase activity may be responsible for a block in the cell cycle and the inability of myocytes to progress through the M phase and subsequently divide.
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Affiliation(s)
- K Reiss
- Department of Medicine and Division of Cardiology, New York Medical College, Valhalla, New York 10595, USA
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38
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Lou H, Zhao Y, Delafontaine P, Kodama T, Katz N, Ramwell PW, Foegh ML. Estrogen effects on insulin-like growth factor-I (IGF-I)-induced cell proliferation and IGF-I expression in native and allograft vessels. Circulation 1997; 96:927-33. [PMID: 9264503 DOI: 10.1161/01.cir.96.3.927] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Estrogen protects against cardiovascular disease in both patients and animal models and regulates insulin-like growth factor-I (IGF-I), an important cell-cycle progression factor. METHODS AND RESULTS Smooth muscle cells and tissues were harvested from male recipient rabbits that 6 weeks earlier had received a cardiac allograft transplant consisting of a donor heart and ascending aorta. Segments of the ascending aorta from the native and allograft hearts from 9 placebo-treated and 8 estradiol-treated recipients were compared by using IGF-I-stimulated [3H]thymidine incorporation. The responses of the native vessel segments were similar (175.3+/-32% and 166.9+/-41%, respectively; P>.05) whether or not the recipients had been treated for 6 weeks with estradiol. In the grafts, however, estradiol markedly inhibited vascular cell thymidine incorporation (328.04+/-56% compared with 67.3+/-11%; P<.02). Smooth muscle cells were derived from the native aorta of the placebo-treated rabbits to study the effect of estradiol in vitro. IGF-I increased cell counts in a concentration-dependent manner. In serum-starved cells estradiol further decreased cell proliferation; this effect was blocked by the specific estrogen receptor antagonist ZK-119.010. Immunohistochemistry staining for IGF-I protein in the coronary arteries and ascending aorta of the cardiac allograft from the placebo-treated recipients revealed extensive IGF-I expression in the myointima. In contrast, IGF-I protein was not expressed in the coronary arteries and ascending aorta of the cardiac allograft from the estradiol-treated recipients. The IGF-I protein was extensively expressed only in the placebo-treated graft vessels. Myointimal thickening of the coronary arteries was significantly reduced by estradiol treatment (17.9+/-1.5% versus 44.3+/-3.7%; P<.02). CONCLUSIONS In vivo estradiol treatment abolishes both IGF-I mitogenic effects and IGF-I protein expression in the vascular wall, which may be causally related to the inhibitory effect of estradiol on transplant arteriosclerosis.
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Affiliation(s)
- H Lou
- Georgetown University Medical Center, Washington, DC 20007, USA
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39
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Affiliation(s)
- S R Umansky
- LXR Biotechnology, Inc. Richmond, California 94804, USA
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40
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Long CS. Autocrine and Paracrine Regulation of Myocardial Cell Growth in Vitro The TGFβ Paradigm. Trends Cardiovasc Med 1996; 6:217-26. [DOI: 10.1016/s1050-1738(96)00090-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Reiss K, Cheng W, Ferber A, Kajstura J, Li P, Li B, Olivetti G, Homcy CJ, Baserga R, Anversa P. Overexpression of insulin-like growth factor-1 in the heart is coupled with myocyte proliferation in transgenic mice. Proc Natl Acad Sci U S A 1996; 93:8630-5. [PMID: 8710922 PMCID: PMC38724 DOI: 10.1073/pnas.93.16.8630] [Citation(s) in RCA: 220] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Transgenic mice were generated in which the cDNA for the human insulin-like growth factor 1B (IGF-1B) was placed under the control of a rat alpha-myosin heavy chain promoter. In mice heterozygous for the transgene, IGF-1B mRNA was not detectable in the fetal heart at the end of gestation, was present in modest levels at 1 day after birth, and increased progressively with postnatal maturation, reaching a peak at 75 days. Myocytes isolated from transgenic mice secreted 1.15 +/- 0.25 ng of IGF-1 per 10(6) cells per 24 hr versus 0.27 +/- 0.10 ng in myocytes from homozygous wild-type littermates. The plasma level of IGF-1 increased 84% in transgenic mice. Heart weight was comparable in wild-type littermates and transgenic mice up to 45 days of age, but a 42%, 45%, 62%, and 51% increase was found at 75, 135, 210, and 300 days, respectively, after birth. At 45, 75, and 210 days, the number of myocytes in the heart was 21%, 31%, and 55% higher, respectively, in transgenic animals. In contrast, myocyte cell volume was comparable in transgenic and control mice at all ages. In conclusion, overexpression of IGF-1 in myocytes leads to cardiomegaly mediated by an increased number of cells in the heart.
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Affiliation(s)
- K Reiss
- Department of Medicine, New York Medical College, Valhalla 10595, USA
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42
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Marino TA, Cao W, Lee J, Courtney R. Localization of proliferating cell nuclear antigen in the developing and mature rat heart cell. Anat Rec (Hoboken) 1996; 245:677-84. [PMID: 8837726 DOI: 10.1002/(sici)1097-0185(199608)245:4<677::aid-ar8>3.0.co;2-l] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND The cardiac muscle cell ceases to divide shortly after birth; this cessation is followed by a limited period when DNA synthesis and karyokinesis occur without cytokinesis. The regulation of this process is not known. The purpose of this study is to explore the possible events that could lead to the cessation of cardiac muscle cell division. One protein requisite for DNA synthesis is proliferating cell nuclear antigen (PCNA). This protein is the auxiliary protein of DNA polymerase delta. METHODS Rats of fetal age day 18 or days 0, 4, 8, 12, and 16 after birth were obtained. In addition, adult hearts were used for this study. Hearts from the fetal day-18 rats and the day-0 neonatal rats were digested. Cardiac myocytes were isolated and placed in culture for an analysis of DNA synthesis by using tridiated thymidine. Ventricular muscle tissue was isolated from hearts of all ages and frozen in liquid nitrogen for Northern and Western blot analyses. RESULTS Tridiated thymidine analysis revealed that, although serum stimulation significantly increased the number of labeled fetal cardiac muscle cells, it did not have that effect on neonatal cardiac muscle cells in culture. Northern blot analysis revealed that the steady state levels of mRNA for PCNA remained constant from fetal day 18 through day 4 after birth. Steady state levels declined during the second postnatal week and then reached basal levels by day 16. PCNA message was still present in adult heart tissue. By using indirect immunofluorescence and Western blotting, PCNA protein could be located in the nucleus of cardiac muscle cells during the first 2 weeks after birth. At 16 days after birth, the protein was found in the cytoplasm in very low amounts but was not found in the nucleus. The protein was barely detectable by Western blotting in the cytoplasmic fraction from the adult myocardium. CONCLUSIONS The results of this study suggest that the PCNA message and protein product declined after birth, but both were present at low levels in the adult myocardium. However, the PCNA protein was not translocated to the nucleus in adult myocardial cells. The events involving PCNA correlated closely with the time period when cell division and then DNA synthesis ceased in these cells.
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Affiliation(s)
- T A Marino
- Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
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Cheng W, Reiss K, Li P, Chun MJ, Kajstura J, Olivetti G, Anversa P. Aging does not affect the activation of the myocyte insulin-like growth factor-1 autocrine system after infarction and ventricular failure in Fischer 344 rats. Circ Res 1996; 78:536-46. [PMID: 8635210 DOI: 10.1161/01.res.78.4.536] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
To determine whether the attenuation in the growth capacity of myocytes in the overloaded aging heart is associated with an impairment in the activation of insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) in the stressed cells, large myocardial infarcts were produced in Fischer 344 rats at 4 and 16 months of age, and the animals were killed 6 hours, 3 days, and 7 days later. After the documentation of cardiac failure, the unaffected myocytes were enzymatically dissociated, and the expression of IGF-1 and IGF-1R was measured at these three time points after surgery. The level of expression of IGF-1R mRNA increased at 3 days and remained elevated at 7 days in both age groups. In addition, an increase in IGF-1R protein in these cells was found, with no apparent difference with age. This phenomenon was coupled with an upregulation of IGF-1 mRNA of comparable magnitude in the younger and older animals. In contrast, the increases in the dimensional properties of myocytes were delayed and of smaller magnitude in the older infarcted rats. Moreover, the expression of atrial natriuretic factor, used as a molecular marker of myocyte cellular hypertrophy, was greater at 3 days in 4-month-old rats and at 7 days in 16-month-old rats. Thus, aging may affect the hypertrophic response of myocytes after infarction but has no impact on the ability of the cells to enhance the expression of IGF-1 and IGF-1R, which may sustain only in part the growth reserve mechanisms of the pathological heart.
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Affiliation(s)
- W Cheng
- Department of Medicine, New York Medical College, Valhalla 10595, USA
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44
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Anversa P, Kajstura J, Reiss K, Quaini F, Baldini A, Olivetti G, Sonnenblick EH. Ischemic cardiomyopathy: myocyte cell loss, myocyte cellular hypertrophy, and myocyte cellular hyperplasia. Ann N Y Acad Sci 1995; 752:47-64. [PMID: 7755292 DOI: 10.1111/j.1749-6632.1995.tb17405.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- P Anversa
- Department of Medicine, New York Medical College, Valhalla 10595, USA
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45
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Quaini F, Cigola E, Lagrasta C, Saccani G, Quaini E, Rossi C, Olivetti G, Anversa P. End-stage cardiac failure in humans is coupled with the induction of proliferating cell nuclear antigen and nuclear mitotic division in ventricular myocytes. Circ Res 1994; 75:1050-63. [PMID: 7955143 DOI: 10.1161/01.res.75.6.1050] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Proliferating cell nuclear antigen (PCNA) is a late growth-regulated gene that is expressed at the G1-S boundary of the cell cycle and is required for DNA synthesis and cell proliferation. Since quantitative results suggest that myocyte hyperplasia occurs in the decompensated human heart, we postulated that induction of the PCNA gene may be present in the failing heart in humans. PCNA protein was detected in myocardial samples obtained from the left and right ventricles of patients with congestive heart failure. Endomyocardial biopsies collected from donor subjects were used as control tissue. The percentage of positively stained myocyte nuclei in the ventricles was established by using PCNA monoclonal antibody and the immunoperoxidase technique. The localization of PCNA in myocytes was confirmed by alpha-sarcomeric actin antibody staining. PCNA labeling was present in left ventricular myocytes of 29 of the 32 hearts examined. In the right ventricle, 24 of the 29 samples showed positive staining. In a subset of 25 patients, the percentage of PCNA-labeled myocyte nuclei was measured and found to constitute 49 +/- 22% of left ventricular myocytes. A similar analysis for the right ventricle, conducted in 21 patients, showed that 49 +/- 19% of the myocyte nuclei exhibited PCNA protein. In addition, mitotic figures in myocytes were documented. A quantitative analysis of this cellular process revealed that 11 myocyte nuclei per 1 million cells exhibited mitotic images in chronic heart failure. Immediately after myocardial infarction, two cells per million showed mitotic division, and this phenomenon was restricted to the region adjacent to the necrotic tissue. No PCNA labeling or nuclear mitotic images were detected in the ventricular myocardium of control subjects. Thus, the observation that diffuse PCNA labeling and myocyte mitotic division are present in hearts with end-stage failure strongly suggests that adult ventricular myocytes are not terminally differentiated cells and that myocyte cellular hyperplasia may constitute a growth reserve mechanism of the diseased heart.
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Affiliation(s)
- F Quaini
- Department of Pathology, University of Parma, Italy
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