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1
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The Roles of Exosomal Proteins: Classification, Function, and Applications. Int J Mol Sci 2023; 24:ijms24043061. [PMID: 36834471 PMCID: PMC9961790 DOI: 10.3390/ijms24043061] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/09/2023] Open
Abstract
Exosome, a subpopulation of extracellular vesicles, plays diverse roles in various biological processes. As one of the most abundant components of exosomes, exosomal proteins have been revealed to participate in the development of many diseases, such as carcinoma, sarcoma, melanoma, neurological disorders, immune responses, cardiovascular diseases, and infection. Thus, understanding the functions and mechanisms of exosomal proteins potentially assists clinical diagnosis and targeted delivery of therapies. However, current knowledge about the function and application of exosomal proteins is still limited. In this review, we summarize the classification of exosomal proteins, and the roles of exosomal proteins in exosome biogenesis and disease development, as well as in the clinical applications.
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Accelerated Growth, Differentiation, and Ploidy with Reduced Proliferation of Right Ventricular Cardiomyocytes in Children with Congenital Heart Defect Tetralogy of Fallot. Cells 2022; 11:cells11010175. [PMID: 35011735 PMCID: PMC8750260 DOI: 10.3390/cells11010175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/29/2021] [Accepted: 01/01/2022] [Indexed: 02/06/2023] Open
Abstract
The myocardium of children with tetralogy of Fallot (TF) undergoes hemodynamic overload and hypoxemia immediately after birth. Comparative analysis of changes in the ploidy and morphology of the right ventricular cardiomyocytes in children with TF in the first years of life demonstrated their significant increase compared with the control group. In children with TF, there was a predominantly diffuse distribution of Connexin43-containing gap junctions over the cardiomyocytes sarcolemma, which redistributed into the intercalated discs as cardiomyocytes differentiation increased. The number of Ki67-positive cardiomyocytes varied greatly and amounted to 7.0–1025.5/106 cardiomyocytes and also were decreased with increased myocytes differentiation. Ultrastructural signs of immaturity and proliferative activity of cardiomyocytes in children with TF were demonstrated. The proportion of interstitial tissue did not differ significantly from the control group. The myocardium of children with TF under six months of age was most sensitive to hypoxemia, it was manifested by a delay in the intercalated discs and myofibril assembly and the appearance of ultrastructural signs of dystrophic changes in the cardiomyocytes. Thus, the acceleration of ontogenetic growth and differentiation of the cardiomyocytes, but not the reactivation of their proliferation, was an adaptation of the immature myocardium of children with TF to hemodynamic overload and hypoxemia.
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3
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Broughton KM, Sussman MA. Adult Cardiomyocyte Cell Cycle Detour: Off-ramp to Quiescent Destinations. Trends Endocrinol Metab 2019; 30:557-567. [PMID: 31262545 PMCID: PMC6703820 DOI: 10.1016/j.tem.2019.05.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/24/2019] [Accepted: 05/30/2019] [Indexed: 02/06/2023]
Abstract
Ability to promote completion of mitotic cycling of adult mammalian cardiomyocytes remains an intractable and vexing challenge, despite being one of the most sought after 'holy grails' of cardiovascular research. While some of the struggle is attributable to adult cardiomyocytes themselves that are notoriously post-mitotic, another contributory factor rests with difficulty in definitive tracking of adult cardiomyocyte cell cycle and lack of rigorous measures to track proliferation in situ. This review summarizes past, present, and future directions to promote adult mammalian cardiomyocyte cell cycle progression, proliferation, and renewal. Establishing relationship(s) between cardiomyocyte cell cycle progression and cellular biological properties is sorely needed to understand the mechanistic basis for cardiomyocyte cell cycle withdrawal to enhance cardiomyocyte cell cycle progression and mitosis.
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Affiliation(s)
- Kathleen M Broughton
- San Diego State University, Department of Biology and Integrated Regenerative Research Institute, San Diego, CA 92182, USA
| | - Mark A Sussman
- San Diego State University, Department of Biology and Integrated Regenerative Research Institute, San Diego, CA 92182, USA.
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4
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Sommese L, Zullo A, Schiano C, Mancini FP, Napoli C. Possible Muscle Repair in the Human Cardiovascular System. Stem Cell Rev Rep 2017; 13:170-191. [PMID: 28058671 DOI: 10.1007/s12015-016-9711-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The regenerative potential of tissues and organs could promote survival, extended lifespan and healthy life in multicellular organisms. Niches of adult stemness are widely distributed and lead to the anatomical and functional regeneration of the damaged organ. Conversely, muscular regeneration in mammals, and humans in particular, is very limited and not a single piece of muscle can fully regrow after a severe injury. Therefore, muscle repair after myocardial infarction is still a chimera. Recently, it has been recognized that epigenetics could play a role in tissue regrowth since it guarantees the maintenance of cellular identity in differentiated cells and, therefore, the stability of organs and tissues. The removal of these locks can shift a specific cell identity back to the stem-like one. Given the gradual loss of tissue renewal potential in the course of evolution, in the last few years many different attempts to retrieve such potential by means of cell therapy approaches have been performed in experimental models. Here we review pathways and mechanisms involved in the in vivo repair of cardiovascular muscle tissues in humans. Moreover, we address the ongoing research on mammalian cardiac muscle repair based on adult stem cell transplantation and pro-regenerative factor delivery. This latter issue, involving genetic manipulations of adult cells, paves the way for developing possible therapeutic strategies in the field of cardiovascular muscle repair.
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Affiliation(s)
- Linda Sommese
- Department of Internal and Specialty Medicine, U.O.C. Clinical Immunology, Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Ospedaliera Universitaria, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia 2, 80138, Naples, Italy.
| | - Alberto Zullo
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy.,CEINGE Advanced Biotechnologies, s.c.ar.l, Naples, Italy
| | | | - Francesco P Mancini
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Claudio Napoli
- Department of Internal and Specialty Medicine, U.O.C. Clinical Immunology, Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Ospedaliera Universitaria, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia 2, 80138, Naples, Italy.,IRCCS Foundation SDN, Naples, Italy
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5
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El-Magd MA, Abdo WS, El-Maddaway M, Nasr NM, Gaber RA, El-Shetry ES, Saleh AA, Alzahrani FAA, Abdelhady DH. High doses of S-methylcysteine cause hypoxia-induced cardiomyocyte apoptosis accompanied by engulfment of mitochondaria by nucleus. Biomed Pharmacother 2017; 94:589-597. [DOI: 10.1016/j.biopha.2017.07.100] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 07/17/2017] [Accepted: 07/20/2017] [Indexed: 12/20/2022] Open
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6
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Cardiomyocyte proliferation in zebrafish and mammals: lessons for human disease. Cell Mol Life Sci 2016; 74:1367-1378. [PMID: 27812722 PMCID: PMC5357290 DOI: 10.1007/s00018-016-2404-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 10/14/2016] [Accepted: 10/28/2016] [Indexed: 01/08/2023]
Abstract
Cardiomyocytes proliferate profusely during early development and for a brief period after birth in mammals. Within a month after birth, this proliferative capability is dramatically reduced in mammals unlike lower vertebrates where it persists into adult life. The zebrafish, for example, retains the ability to regenerate the apex of the heart following resection by a mechanism predominantly driven by cardiomyocyte proliferation. Differences in proliferative capacity of cardiomyocytes in adulthood between mammals and lower vertebrates are closely liked to ontogenetic or phylogenetic factors. Elucidation of these factors has the potential to provide enormous benefits if they lead to the development of therapeutic strategies that facilitate cardiomyocyte proliferation. In this review, we highlight the differences between Mammalian and Zebrafish cardiomyocytes, which could explain at least in part the different proliferative capacities in these two species. We discuss the advantages of the zebrafish as a model of cardiomyocyte proliferation, particularly at the embryonic stage. We also identify a number of key molecular pathways with potential to reveal key steps in switching cardiomyocytes from a quiescent to a proliferative phenotype.
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Brunner R, Lai HL, Deliu Z, Melman E, Geenen DL, Wang QT. Asxl2 -/- Mice Exhibit De Novo Cardiomyocyte Production during Adulthood. J Dev Biol 2016; 4:jdb4040032. [PMID: 29615595 PMCID: PMC5831801 DOI: 10.3390/jdb4040032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 10/26/2016] [Accepted: 10/27/2016] [Indexed: 12/20/2022] Open
Abstract
Heart attacks affect more than seven million people worldwide each year. A heart attack, or myocardial infarction, may result in the death of a billion cardiomyocytes within hours. The adult mammalian heart does not have an effective mechanism to replace lost cardiomyocytes. Instead, lost muscle is replaced with scar tissue, which decreases blood pumping ability and leads to heart failure over time. Here, we report that the loss of the chromatin factor ASXL2 results in spontaneous proliferation and cardiogenic differentiation of a subset of interstitial non-cardiomyocytes. The adult Asxl2-/- heart displays spontaneous overgrowth without cardiomyocyte hypertrophy. Thymidine analog labeling and Ki67 staining of 12-week-old hearts revealed 3- and 5-fold increases of proliferation rate for vimentin⁺ non-cardiomyocytes in Asxl2-/- over age- and sex-matched wildtype controls, respectively. Approximately 10% of proliferating non-cardiomyocytes in the Asxl2-/- heart express the cardiogenic marker NKX2-5, a frequency that is ~7-fold higher than that observed in the wildtype. EdU lineage tracing experiments showed that ~6% of pulsed-labeled non-cardiomyocytes in Asxl2-/- hearts differentiate into mature cardiomyocytes after a four-week chase, a phenomenon not observed for similarly pulse-chased wildtype controls. Taken together, these data indicate de novo cardiomyocyte production in the Asxl2-/- heart due to activation of a population of proliferative cardiogenic non-cardiomyocytes. Our study suggests the existence of an epigenetic barrier to cardiogenicity in the adult heart and raises the intriguing possibility of unlocking regenerative potential via transient modulation of epigenetic activity.
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Affiliation(s)
- Rachel Brunner
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
| | - Hsiao-Lei Lai
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
- PTM Biolabs Inc., Chicago, IL 60612, USA.
| | - Zane Deliu
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
| | - Elan Melman
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
- The School of Molecular and Cellular Biology, University of Illinois Urbana-Champaign, Champaign, IL 61801, USA.
| | - David L Geenen
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
- Physician Assistant Studies, Grand Valley State University, Grand Rapids, MI 49503, USA.
| | - Q Tian Wang
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
- Congressionally Directed Medical Research Programs, Frederick, MD 21702, USA.
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Bruyneel AAN, Sehgal A, Malandraki-Miller S, Carr C. Stem Cell Therapy for the Heart: Blind Alley or Magic Bullet? J Cardiovasc Transl Res 2016; 9:405-418. [PMID: 27542008 PMCID: PMC5153828 DOI: 10.1007/s12265-016-9708-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 08/05/2016] [Indexed: 12/15/2022]
Abstract
When stressed by ageing or disease, the adult human heart is unable to regenerate, leading to scarring and hypertrophy and eventually heart failure. As a result, stem cell therapy has been proposed as an ultimate therapeutic strategy, as stem cells could limit adverse remodelling and give rise to new cardiomyocytes and vasculature. Unfortunately, the results from clinical trials to date have been largely disappointing. In this review, we discuss the current status of the field and describe various limitations and how future work may attempt to resolve these to make way to successful clinical translation.
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Affiliation(s)
- Arne A N Bruyneel
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
| | | | | | - Carolyn Carr
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
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Studzian K, Kik K, Lukawska M, Oszczapowicz I, Strek M, Szmigiero L. Subcellular localization of anthracyclines in cultured rat cardiomyoblasts as possible predictors of cardiotoxicity. Invest New Drugs 2015; 33:1032-9. [PMID: 26268925 PMCID: PMC4768221 DOI: 10.1007/s10637-015-0276-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 08/06/2015] [Indexed: 11/29/2022]
Abstract
In this study, we compared the cellular uptake, intracellular localization and cytotoxicity of two groups of anthracycline derivatives in cultured H9c2(2-1) rat cardiomyoblasts. The first group consisted of doxorubicin (DOX) and two of its derivatives containing a formamidino group (–N = CH–N<) at the C-3′ position with a morpholine (DOXM) or a hexamethyleneimine (DOXH) ring. The second group consisted of daunorubicin (DRB) and its derivatives containing a morpholine (DRBM) or a hexamethyleneimine (DRBH) ring. DOXH and DRBH were taken up by cardiomyoblasts more efficiently than estimated for other tested anthracyclines. The cellular uptakes of DOXM and DRBM were reduced compared to those of the parent compounds. Applied structural modifications of DOX and DRB influenced the subcellular localization of the tested derivatives. DOX and DOXH were localized primarily in nuclei, whereas the other anthracyclines were found in the nuclei and cytoplasm. The percentages of the compounds that accumulated in the nuclei were 80.2 and 54.2 % for DOX and DOXH, respectively. The lowest nuclear accumulation values were observed for DRBM (19.9 %), DRBH (21.9 %) and DOXM (23.7 %). The ability of anthracyclines to accumulate in the nuclei correlated with their DNA binding constants (r = 0.858, P = 0.029). A correlation was found between the accumulation of the tested anthracyclines in the nuclei of cardiomyoblasts and their cardiotoxicity in vivo, which was observed in our previous study. We suggest that cytotoxicity and the anthracycline accumulation level in the nuclei of cultured cardiomyoblasts could be used for early prediction of their cardiotoxicity.
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Affiliation(s)
- Kazimierz Studzian
- Department of Nucleic Acids Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213, Lodz, Poland
| | - Krzysztof Kik
- Department of Nucleic Acids Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213, Lodz, Poland
| | - Malgorzata Lukawska
- Institute of Biotechnology and Antibiotics, 5 Staroscinska St., 02-516, Warsaw, Poland
| | - Irena Oszczapowicz
- Institute of Biotechnology and Antibiotics, 5 Staroscinska St., 02-516, Warsaw, Poland
| | - Malgorzata Strek
- Department of Nucleic Acids Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213, Lodz, Poland
| | - Leszek Szmigiero
- Department of Nucleic Acids Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213, Lodz, Poland.
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10
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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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11
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Abstract
This review article discusses the mechanisms of cardiomyogenesis in the adult heart. They include the re-entry of cardiomyocytes into the cell cycle; dedifferentiation of pre-existing cardiomyocytes, which assume an immature replicating cell phenotype; transdifferentiation of hematopoietic stem cells into cardiomyocytes; and cardiomyocytes derived from activation and lineage specification of resident cardiac stem cells. The recognition of the origin of cardiomyocytes is of critical importance for the development of strategies capable of enhancing the growth response of the myocardium; in fact, cell therapy for the decompensated heart has to be based on the acquisition of this fundamental biological knowledge.
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Affiliation(s)
- Annarosa Leri
- From the Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
| | - Marcello Rota
- From the Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Francesco S Pasqualini
- From the Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Polina Goichberg
- From the Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Piero Anversa
- From the Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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12
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13
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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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Fiedler LR, Maifoshie E, Schneider MD. Mouse models of heart failure: cell signaling and cell survival. Curr Top Dev Biol 2014; 109:171-247. [PMID: 24947238 DOI: 10.1016/b978-0-12-397920-9.00002-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Heart failure is one of the paramount global causes of morbidity and mortality. Despite this pandemic need, the available clinical counter-measures have not altered substantially in recent decades, most notably in the context of pharmacological interventions. Cell death plays a causal role in heart failure, and its inhibition poses a promising approach that has not been thoroughly explored. In previous approaches to target discovery, clinical failures have reflected a deficiency in mechanistic understanding, and in some instances, failure to systematically translate laboratory findings toward the clinic. Here, we review diverse mouse models of heart failure, with an emphasis on those that identify potential targets for pharmacological inhibition of cell death, and on how their translation into effective therapies might be improved in the future.
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Affiliation(s)
- Lorna R Fiedler
- British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Imperial College London, London, UK.
| | - Evie Maifoshie
- British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Imperial College London, London, UK
| | - Michael D Schneider
- British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Imperial College London, London, UK.
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15
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Tallawi M, Rai R, R-Gleixner M, Roerick O, Weyand M, Roether JA, Schubert DW, Kozlowska A, Fray ME, Merle B, Göken M, Aifantis K, Boccaccini AR. Poly(glycerol sebacate)\Poly(butylene succinate-dilinoleate) Blends as Candidate Materials for Cardiac Tissue Engineering. ACTA ACUST UNITED AC 2013. [DOI: 10.1002/masy.201300114] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- M. Tallawi
- Institute of Biomaterials; Department of Materials Science and Engineering; University of Erlangen-Nuremberg; 91058 Erlangen Germany
| | - R. Rai
- Institute of Biomaterials; Department of Materials Science and Engineering; University of Erlangen-Nuremberg; 91058 Erlangen Germany
| | - M. R-Gleixner
- Department of Cardiac Surgery; University of Erlangen-Nuremberg; 91054 Erlangen Germany
| | - O. Roerick
- Department of Cardiac Surgery; University of Erlangen-Nuremberg; 91054 Erlangen Germany
| | - M. Weyand
- Department of Cardiac Surgery; University of Erlangen-Nuremberg; 91054 Erlangen Germany
| | - J. A. Roether
- Institute of Polymeric Materials; Department of Materials Science and Engineering; University of Erlangen-Nuremberg; 91058 Erlangen Germany
| | - D. W. Schubert
- Institute of Polymeric Materials; Department of Materials Science and Engineering; University of Erlangen-Nuremberg; 91058 Erlangen Germany
| | - A. Kozlowska
- Polymer Institute; Division of Biomaterials and Microbiological Technologies; West Pomeranian University of Technology; Szczecin Poland
| | - M. El Fray
- Polymer Institute; Division of Biomaterials and Microbiological Technologies; West Pomeranian University of Technology; Szczecin Poland
| | - B. Merle
- Institute of General Materials Properties; Department of Materials Science and Engineering; University of Erlangen-Nuremberg; 91058 Erlangen Germany
| | - M. Göken
- Institute of General Materials Properties; Department of Materials Science and Engineering; University of Erlangen-Nuremberg; 91058 Erlangen Germany
| | - K. Aifantis
- Lab of Mechanics and Materials; School of Engineering; Aristotle University of Thessaloniki; 54124 Thessaloniki Greece
| | - A. R. Boccaccini
- Institute of Biomaterials; Department of Materials Science and Engineering; University of Erlangen-Nuremberg; 91058 Erlangen Germany
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16
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Rai R, Tallawi M, Barbani N, Frati C, Madeddu D, Cavalli S, Graiani G, Quaini F, Roether JA, Schubert DW, Rosellini E, Boccaccini AR. Biomimetic poly(glycerol sebacate) (PGS) membranes for cardiac patch application. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2013; 33:3677-87. [DOI: 10.1016/j.msec.2013.04.058] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 04/12/2013] [Accepted: 04/26/2013] [Indexed: 10/26/2022]
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Abstract
Stem cell therapy for cardiac disease is an exciting but highly controversial research area. Strategies such as cell transplantation and reprogramming have demonstrated both intriguing and sobering results. Yet as clinical trials proceed, our incomplete understanding of stem cell behavior is made evident by numerous unresolved matters, such as the mechanisms of cardiomyocyte turnover or the optimal therapeutic strategies to achieve clinical efficacy. In this Perspective, we consider how cardiac stem cell biology has led us into clinical trials, and we suggest that achieving true cardiac regeneration in patients may ultimately require resolution of critical controversies in experimental cardiac regeneration.
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Affiliation(s)
- Jessica C. Garbern
- Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA
| | - Richard T. Lee
- Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
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18
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Zhao X, Huang L. Cardiac stem cells: A promising treatment option for heart failure. Exp Ther Med 2012; 5:379-383. [PMID: 23407679 PMCID: PMC3570189 DOI: 10.3892/etm.2012.854] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Accepted: 10/18/2012] [Indexed: 12/25/2022] Open
Abstract
Cardiovascular diseases are the most common cause of death in the world. The development of heart failure is mainly due to the loss of cardiomyocytes following myocardial infarction and the absence of endogenous myocardial repair. Numerous studies have focused on cardiac stem cells (CSCs) due to their therapeutic benefit, particularly in the treatment of heart failure. It has previously been demonstrated that CSCs are able to promote the regeneration of cardiomyocytes in animals following myocardial infarction. However, the underlying mechanism(s) remain unclear. This review mainly discusses the cardioprotective effect of CSCs and the effect of CSCs on the function of cardiomyocytes, and compares the efficacies of CSCs from rats, mice and humans, thereby contributing to an improved understanding of CSCs as a promising treatment option for heart failure.
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Affiliation(s)
- Xiaohui Zhao
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
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20
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Agostini S, Recchia FA, Lionetti V. Molecular advances in reporter genes: the need to witness the function of stem cells in failing heart in vivo. Stem Cell Rev Rep 2012; 8:503-12. [PMID: 21732091 DOI: 10.1007/s12015-011-9296-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Stem cells possess the ability to terminally differentiate in cell phenotypes belonging to several different lineages. Over the last decade, transplant of adult stem cells into the injuried myocardium has been widely studied as a revolutionary approach to promote the non-pharmacological improvement or replacement of the lost function. In spite of the tantalizing perspectives and controversial results, several questions about the viability and biology of transplanted stem cells in the beating heart still remain unanswered, mostly because of the current technological limitations. Recent advances in bio- and nano-technology are allowing the development of molecular probes for imaging thus providing a better understanding of stem cells physiology and fate in vivo. Reporter gene based molecular imaging is a high-throughput and sensitive tool used to unscramble over time the mechanisms underlying cell-induced myocardial repair in vivo. To date, the employed reporter genes have been exogenous (proteins which are expressed after gene engineering), or endogenous (detected by tracer substrates). This review will highlight current and outstanding experimental investigations, which are developing new probes to monitor the fate of stem cells transplanted in failing myocardium in vivo.
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Affiliation(s)
- Silvia Agostini
- Laboratory of Medical Science, Institute for Life Sciences, Scuola Superiore Sant'Anna, via G Moruzzi 1, 56124 Pisa, Italy
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Down-regulation of replication factor C-40 (RFC40) causes chromosomal missegregation in neonatal and hypertrophic adult rat cardiac myocytes. PLoS One 2012; 7:e39009. [PMID: 22720015 PMCID: PMC3375256 DOI: 10.1371/journal.pone.0039009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 05/15/2012] [Indexed: 11/25/2022] Open
Abstract
Background Adult mammalian cardiac myocytes are generally assumed to be terminally differentiated; nonetheless, a small fraction of cardiac myocytes have been shown to replicate during ventricular remodeling. However, the expression of Replication Factor C (RFC; RFC140/40/38/37/36) and DNA polymerase δ (Pol δ) proteins, which are required for DNA synthesis and cell proliferation, in the adult normal and hypertrophied hearts has been rarely studied. Methods We performed qRT-PCR and Western blot analysis to determine the levels of RFC and Pol δ message and proteins in the adult normal cardiac myocytes and cardiac fibroblasts, as well as in adult normal and pulmonary arterial hypertension induced right ventricular hypertrophied hearts. Immunohistochemical analyses were performed to determine the localization of the re-expressed DNA replication and cell cycle proteins in adult normal (control) and hypertrophied right ventricle. We determined right ventricular cardiac myocyte polyploidy and chromosomal missegregation/aneuploidy using Fluorescent in situ hybridization (FISH) for rat chromosome 12. Results RFC40-mRNA and protein was undetectable, whereas Pol δ message was detectable in the cardiac myocytes isolated from control adult hearts. Although RFC40 and Pol δ message and protein significantly increased in hypertrophied hearts as compared to the control hearts; however, this increase was marginal as compared to the fetal hearts. Immunohistochemical analyses revealed that in addition to RFC40, proliferative and mitotic markers such as cyclin A, phospho-Aurora A/B/C kinase and phospho-histone 3 were also re-expressed/up-regulated simultaneously in the cardiac myocytes. Interestingly, FISH analyses demonstrated cardiac myocytes polyploidy and chromosomal missegregation/aneuploidy in these hearts. Knock-down of endogenous RFC40 caused chromosomal missegregation/aneuploidy and decrease in the rat neonatal cardiac myocyte numbers. Conclusion Our novel findings suggest that transcription of RFC40 is suppressed in the normal adult cardiac myocytes and its insufficient re-expression may be responsible for causing chromosomal missegregation/aneuploidy and in cardiac myocytes during right ventricular hypertrophy.
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Aviv Y, Shaw J, Gang H, Kirshenbaum LA. Regulation of autophagy in the heart: "you only live twice". Antioxid Redox Signal 2011; 14:2245-50. [PMID: 20712404 DOI: 10.1089/ars.2010.3479] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Autophagy is a highly orchestrated cellular process by which proteins and organelles are degraded via an elaborate lysosomal pathway to generate free amino acids and sugars for ATP during metabolic stress. At present, the exact role of autophagy in the heart is highly debated but suggested to play a key role in regulating cell turnover in cardiomyopathies and heart failure. The signaling pathways and molecular effectors that govern autophagy are incomplete, as are the mechanisms that determine whether autophagy promotes or prevents cell death. The mitochondrion has been identified as a key organelle centrally involved in regulating autophagy. Certain members of the Bcl-2 gene family, including Beclin-1, Bcl-2 nineteen kilodaltons interacting protein (Bnip3), and Nix/Bnip3L, provoke mitochondrial perturbations leading to permeability transition pore opening, resulting in apoptosis, autophagy, or both. These and other aspects of autophagy processes have been discussed.
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Affiliation(s)
- Yaron Aviv
- Department of Pharmacology and Therapeutics, The Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada
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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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Tiangco DA, Halcomb S, Lattanzio FA, Hargrave BY. 3,4-Methylenedioxymethamphetamine alters left ventricular function and activates nuclear factor-Kappa B (NF-κB) in a time and dose dependent manner. Int J Mol Sci 2010; 11:4843-63. [PMID: 21614177 PMCID: PMC3100831 DOI: 10.3390/ijms11124743] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Revised: 11/04/2010] [Accepted: 11/08/2010] [Indexed: 11/16/2022] Open
Abstract
3,4-Methylenedioxymethamphetamine (MDMA) is an illicit psychoactive drug with cardiovascular effects that have not been fully described. In the current study, we observed the effects of acute MDMA on rabbit left ventricular function. We also observed the effects of MDMA on nuclear factor-kappa B (NF-κB) activity in cultured rat ventricular myocytes (H9c2). In the rabbit, MDMA (2 mg/kg) alone caused a significant increase in heart rate and a significant decrease in the duration of the cardiac cycle. Inhibition of nitric oxide synthase (NOS) by pretreatment with L-NAME (10 mg/kg) alone caused significant dysfunction in heart rate, systolic pressure, diastolic pressure, duration of relaxation, duration of cardiac cycle, and mean left ventricular pressure. Pretreatment with L-NAME followed by treatment with MDMA caused significant dysfunction in additional parameters that were not abnormal upon exposure to either compound in isolation: duration of contraction, inotropy, and pulse pressure. Exposure to 1.0 mM MDMA for 6 h or 2.0 μM MDMA for 12 h caused increased nuclear localization of NF-κB in cultured H9c2 cells. The current results suggest that MDMA is acutely detrimental to heart function and that an intact cardiovascular NOS system is important to help mitigate early sequelae in some functional parameters. The delayed timing of NF-κB activation suggests that this factor may be relevant to MDMA induced cardiomyopathy of later onset.
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Affiliation(s)
- David A. Tiangco
- Department of Biological Sciences, Old Dominion University, Norfolk, VA 23529, USA
| | - Sapna Halcomb
- Department of Biological Sciences, Old Dominion University, Norfolk, VA 23529, USA
| | - Frank A. Lattanzio
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, 23510, USA
| | - Barbara Y. Hargrave
- Department of Biological Sciences, Old Dominion University, Norfolk, VA 23529, USA
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25
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Carvalho AB, de Carvalho ACC. Heart regeneration: Past, present and future. World J Cardiol 2010; 2:107-111. [PMID: 21160711 PMCID: PMC2999050 DOI: 10.4330/wjc.v2.i5.107] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Revised: 03/30/2010] [Accepted: 04/06/2010] [Indexed: 02/06/2023] Open
Abstract
The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century. We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified, culminating with the report that we renew 50% of our cardiomyocytes during our lifetime. The future of cardiac regenerative therapies is discussed, presenting the difficulties to overcome before repair of the diseased heart can come into clinical practice.
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Affiliation(s)
- Adriana Bastos Carvalho
- Adriana Bastos Carvalho, Antonio Carlos Campos de Carvalho, National Institute of Cardiology, Rio de Janeiro, RJ, CEP 22240-006, Brazil; Carlos Chagas Filho Institute of Biophysics and Institute for Science and Technology in Structural Biology and Bioimaging, Rio de Janeiro, RJ, CEP 21941-902, Brazil
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Nakamura H, Tokumoto M, Mizobuchi M, Ritter CS, Finch JL, Mukai M, Slatopolsky E. Novel markers of left ventricular hypertrophy in uremia. Am J Nephrol 2010; 31:292-302. [PMID: 20130393 DOI: 10.1159/000279768] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Accepted: 12/04/2009] [Indexed: 01/17/2023]
Abstract
AIMS Left ventricular hypertrophy (LVH) is the most frequent cardiac complication in chronic renal disease. Previous studies implicate elevated serum phosphorus as a risk factor for LVH. METHODS We treated 5/6 nephrectomized rats with enalapril or enalapril + sevelamer carbonate for 4 months to determine if sevelamer carbonate had an additional beneficial effect on the development of LVH and uremia-induced left ventricle (LV) remodeling. RESULTS Uremia increased LV weight and cardiomyocyte size. Enalapril and enalapril + sevelamer blunted the increase in left ventricular weight. Only enalapril + sevelamer diminished the increase in cardiomyocyte size. Uremia increased cyclin D2 and PCNA and decreased p27 protein expression in the heart. Enalapril + sevelamer diminished the decrease in p27 expression caused by uremia. Uremia increased Ki67-positive and phosphohistone H(3)-positive interstitial cells. This was not seen in cardiomyocytes. Multivariable regression analysis showed that increased phosphorus was an independent risk factor for both increased LV weight and cardiomyocyte size. CONCLUSIONS These data suggest left ventricular remodeling consists of cardiomyocyte hypertrophy and interstitial cell proliferation, but not cardiomyocyte proliferation. p27 and cyclin D2 may play important roles in the development of LVH. In addition, phosphorus can be an independent risk factor for the development of LVH.
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Kolwicz SC, MacDonnell SM, Renna BF, Reger PO, Seqqat R, Rafiq K, Kendrick ZV, Houser SR, Sabri A, Libonati JR. Left ventricular remodeling with exercise in hypertension. Am J Physiol Heart Circ Physiol 2009; 297:H1361-8. [PMID: 19666835 DOI: 10.1152/ajpheart.01253.2008] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We investigated how exercise training superimposed on chronic hypertension impacted left ventricular remodeling. Cardiomyocyte hypertrophy, apoptosis, and proliferation in hearts from female spontaneously hypertensive rats (SHRs) were examined. Four-month-old SHR animals were placed into a sedentary group (SHR-SED; n = 18) or a treadmill running group (SHR-TRD, 20 m/min, 1 h/day, 5 days/wk, 12 wk; n = 18). Age-matched, sedentary Wistar Kyoto (WKY) rats were controls (n = 18). Heart weight was greater in SHR-TRD vs. both WKY (P < 0.01) and SHR-SED (P < 0.05). Morphometric-derived left ventricular anterior, posterior, and septal wall thickness were increased in SHR-SED relative to WKY and augmented in SHR-TRD. Cardiomyocyte surface area, length, and width were increased in SHR-SED relative to WKY and further increased in SHR-TRD. Calcineurin abundance was increased in SHR-SED vs. WKY (P < 0.001) and attenuated in SHR-TRD relative to SHR-SED (P < 0.05). Protein abundance and mRNA of Akt was not different among groups. The rate of apoptosis was increased in SHR-SED relative to WKY and mitigated in SHR-TRD. The abundance of Ki-67(+) cells across groups was not statistically different across groups. The abundance of cardiac progenitor cells (c-Kit(+) cells) was increased in SHR-TRD relative to WKY. These data suggest that exercise training superimposed on hypertension augmented cardiomyocyte hypertrophy, despite attenuating calcineurin abundance. Exercise training also mitigated apoptosis in hypertension and showed a tendency to enhance the abundance of cardiac progenitor cells, resulting in a more favorable cardiomyocyte number in the exercise-trained hypertensive heart.
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Affiliation(s)
- Stephen C Kolwicz
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Abstract
At present the prevalence of heart failure rises along with aging of the population. Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β-blockers, angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies. In this review two of emerging therapies in the treatment of heart failure are discussed: metabolic modulation and cellular therapy. Metabolic modulation aims to optimize the myocardial energy utilization via shifting the substrate utilization from free fatty acids to glucose. Cellular therapy on the other hand has the goal to achieve true cardiac regeneration. We review the experimental data that support these strategies as well as the available pharmacological agents for metabolic modulation and clinical application of cellular therapy.
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Affiliation(s)
- Diana Revenco
- Division of Cardiovascular Medicine, Caritas St. Elizabeth's Medical Center, Boston, MA 02135, USA
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29
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Laguens RP, Crottogini AJ. Cardiac regeneration: the gene therapy approach. Expert Opin Biol Ther 2009; 9:411-25. [DOI: 10.1517/14712590902806364] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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van Amerongen MJ, Engel FB. Features of cardiomyocyte proliferation and its potential for cardiac regeneration. J Cell Mol Med 2008; 12:2233-44. [PMID: 18662194 PMCID: PMC4514102 DOI: 10.1111/j.1582-4934.2008.00439.x] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The human heart does not regenerate. Instead, following injury, human hearts scar. The loss of contractile tissue contributes significantly to morbidity and mortality. In contrast to humans, zebrafish and newts faithfully regenerate their hearts. Interestingly, regeneration is in both cases based on cardiomyocyte proliferation. In addition, mammalian cardiomyocytes proliferate during foetal development. Their proliferation reaches its maximum around chamber formation, stops shortly after birth, and subsequent heart growth is mostly achieved by an increase in cardiomyocyte size (hypertrophy). The underlying mechanisms that regulate cell cycle arrest and the switch from proliferation to hypertrophy are unclear. In this review, we highlight features of dividing cardiomyocytes, summarize the attempts to induce mammalian cardiomyocyte proliferation, critically discuss methods commonly used for its detection, and explore the potential and problems of inducing cardiomyocyte proliferation to improve function in diseased hearts.
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Affiliation(s)
- Machteld J van Amerongen
- Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
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31
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Pereira LMM, Mandarim-de-Lacerda CA. The effect of enalapril and verapamil on the left ventricular hypertrophy and the left ventricular cardiomyocyte numerical density in rats submitted to nitric oxide inhibition. Int J Exp Pathol 2008. [DOI: 10.1111/j.1365-2613.2001.iep172.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Smith RR, Barile L, Messina E, Marbán E. Stem cells in the heart: what's the buzz all about?--Part 1: preclinical considerations. Heart Rhythm 2008; 5:749-57. [PMID: 18452881 DOI: 10.1016/j.hrthm.2008.02.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2007] [Accepted: 02/02/2008] [Indexed: 10/22/2022]
Abstract
New approaches for cardiac repair have been enabled by the discovery that the heart contains its own reservoir of stem cells. These cells are positive for various stem/progenitor cell markers, are self-renewing, and exhibit multilineage differentiation potential. Recently we developed a method for ex vivo expansion of cardiac-derived stem cells from human myocardial biopsies with a view to subsequent autologous transplantation for myocardial regeneration. Here we review the state of the cardiac stem cell field and our own work on cardiosphere-derived stem cells from human hearts. The first of this two-part review outlines emerging preclinical data on the application of cardiac stem cells. Part 2 continues with a discussion of other stem cell sources with clinical potential, a summary of the critical issues surrounding stem cell therapy (with an emphasis on the crucial issue of how cell transplantation may influence arrhythmias), our perception of clinical stem cell trials to date, and the issues facing the clinical application of cardiac stem cells.
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Nozyński J, Zakliczyński M, Zembala-Nozyńska E, Konecka-Mrówka D, Przybylski R, Nikiel B, Lange D, Mrówka A, Przybylski J, Maruszewski M, Zembala M. Remodeling of human transplanted myocardium in ten-year follow-up: a clinical pathology study. Transplant Proc 2008; 39:2833-40. [PMID: 18021996 DOI: 10.1016/j.transproceed.2007.08.074] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
UNLABELLED Remodeling taking place in transplanted myocardium leads to a change in the number of cardiocytes. Ultrasound measurements and biopsy evaluation should reflect their loss and compensation. We sought to evaluate the morphology of the transplanted heart upon long-term follow-up. MATERIAL AND METHODS Myocardial biopsies were obtained in the first week, first month, and then annually for 10 years from transplantation that did not show rejection (grade "0" ISHLT, 122 biopsies). The control group encompassed 7 donor heart fragments. Proliferation in biopsies was evaluated with Ki67 (M7240, DAKO), cardiocyte hypertrophy by measuring their diameter, the surface area of the nuclei, nuclear-sarcoplasmic index, and stromal fibrosis evaluated as the surface area fraction. Ultrasound measurements included diastolic thickness of the interventricular septum, posterior wall of the left ventricle, and left ventricular mass. The correlation of measurements with time from transplantation was evaluated using Spearman's test. RESULTS A positive Ki67 reaction was observed in fibroblasts and endothelial cells. The increased cardiocyte nuclear area correlated with the time elapsed since transplantation (r = 0.2; P < .05) with a simultaneous decrease in cardiocyte thickness (r = -0.3; P < .05), without changes in the nuclear-cytoplasmic index (r = 0.02; P > .05). Stromal fibrosis also increased (r = 0.1; P < .05). Ultrasound measurements of the left ventricle showed a decreased tendency with the passage of time (r = -0.2 to -0.3; P < .05). CONCLUSION A transplanted heart does not undergo hypertrophy but rather fibrous atrophy with apparent compensatory hypertrophy of the cardiomyocytes.
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Affiliation(s)
- J Nozyński
- Department of Cardiac Surgery & Transplantation, Silesian Center for Heart Disease, Zabrze, Poland
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Stilli D, Lagrasta C, Berni R, Bocchi L, Savi M, Delucchi F, Graiani G, Monica M, Maestri R, Baruffi S, Rossi S, Macchi E, Musso E, Quaini F. Preservation of ventricular performance at early stages of diabetic cardiomyopathy involves changes in myocyte size, number and intercellular coupling. Basic Res Cardiol 2007; 102:488-99. [PMID: 17585379 DOI: 10.1007/s00395-007-0665-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2007] [Revised: 05/03/2007] [Accepted: 05/23/2007] [Indexed: 01/07/2023]
Abstract
In a rat model of diabetic cardiomyopathy, we tested whether specific changes in myocyte turnover and intercellular coupling contribute to preserving ventricular performance after a short period of hyperglycemia. In 41 rats with streptozotocin-induced diabetes and 24 control animals, cardiac electromechanical properties were assessed by telemetry ECG, epicardial potential mapping, and hemodynamic measurements to document normal ventricular function. Myocardial remodeling, expression of gap-junction proteins and myocyte regeneration were evaluated by tissue morphometry, immunohistochemistry and immunoblotting. Ventricular myocyte number and volume were also determined. In diabetic hearts, after 3 weeks of hyperglycemia, left ventricular mass was lowered by 23%, while left ventricular wall thickness and chamber volume were maintained, in the absence of fibrosis and myocyte hypertrophy. In the presence of a marked DNA oxidative damage, an increased rate of DNA replication and mitotic divisions associated with generation of new myocytes were detected. The number of cells expressing the receptor for Stem Cell Factor (c-kit) and their rate of proliferation were preserved in the left ventricle while the atrial storage of these primitive cells was severely reduced by diabetes-induced oxidative stress. Despite a down-regulation of Connexin43 and over-expression of both Connexin40 and Connexin45, the junctional proteins were normally distributed in diabetic ventricular myocardium,justifying the preserved tissue excitability and conduction velocity. In conclusion, before the appearance of the diabetic cardiomyopathic phenotype,myocardial cell proliferation associated with gap junction protein remodeling may contribute to prevent marked alterations of cardiac structure and electrophysiological properties, preserving ventricular performance.
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Affiliation(s)
- Donatella Stilli
- Dept of Evolutionary and Functional, Biology-Physiology Section, University of Parma, Parma, Italy.
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Bicknell KA, Coxon CH, Brooks G. Can the cardiomyocyte cell cycle be reprogrammed? J Mol Cell Cardiol 2007; 42:706-21. [PMID: 17362983 DOI: 10.1016/j.yjmcc.2007.01.006] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2006] [Revised: 01/02/2007] [Accepted: 01/16/2007] [Indexed: 10/23/2022]
Abstract
Cardiac repair following myocardial injury is restricted due to the limited proliferative potential of adult cardiomyocytes. The ability of mammalian cardiomyocytes to proliferate is lost shortly after birth as cardiomyocytes withdraw from the cell cycle and differentiate. We do not fully understand the molecular and cellular mechanisms that regulate this cell cycle withdrawal, although if we could it might lead to the discovery of novel therapeutic targets for improving cardiac repair following myocardial injury. For the last decade, researchers have investigated cardiomyocyte cell cycle control, commonly using transgenic mouse models or recombinant adenoviruses to manipulate cell cycle regulators in vivo or in vitro. This review discusses cardiomyocyte cell cycle regulation and summarises recent data from studies manipulating the expressions and activities of cell cycle regulators in cardiomyocytes. The validity of therapeutic strategies that aim to reinstate the proliferative potential of cardiomyocytes to improve myocardial repair following injury will be discussed.
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Affiliation(s)
- Katrina A Bicknell
- School of Pharmacy, University of Reading, PO Box 226 Whiteknights, Reading Berkshire RG6 6AP, UK.
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Anversa P, Leri A, Rota M, Hosoda T, Bearzi C, Urbanek K, Kajstura J, Bolli R. Concise review: stem cells, myocardial regeneration, and methodological artifacts. Stem Cells 2006; 25:589-601. [PMID: 17124006 DOI: 10.1634/stemcells.2006-0623] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
This review discusses the current controversy about the role that endogenous and exogenous progenitor cells have in cardiac homeostasis and myocardial regeneration following injury. Although great enthusiasm was created by the possibility of reconstituting the damaged heart, the opponents of this new concept of cardiac biology have interpreted most of the findings supporting this possibility as the product of technical artifacts. This article challenges this established, static view of cardiac growth and favors the notion that the mammalian heart has the inherent ability to replace its cardiomyocytes through the activation of a pool of resident primitive cells or the administration of hematopoietic stem cells.
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Affiliation(s)
- Piero Anversa
- Cardiovascular Research Institute, Vosburgh Pavilion, New York Medical College, Valhalla, NY 10595, USA.
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Kunapuli S, Rosanio S, Schwarz ER. "How do cardiomyocytes die?" apoptosis and autophagic cell death in cardiac myocytes. J Card Fail 2006; 12:381-91. [PMID: 16762802 DOI: 10.1016/j.cardfail.2006.02.002] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2005] [Revised: 01/11/2006] [Accepted: 02/02/2006] [Indexed: 11/25/2022]
Abstract
BACKGROUND Cell death constitutes one of the key events in biology. Historically, apoptosis and necrosis have been considered to represent the 2 fundamental forms of cell death. Apoptosis is a tightly regulated, energy-dependent process in which cell death follows a programmed set of events. Necrosis refers to the sum of degenerative changes that follow any type of cell death. METHODS AND RESULTS The role of apoptosis in development of ischemic heart disease, hypertensive heart disease, and end-stage heart failure has been well documented. Recent evidence suggests the potential role of a third mechanism of cell death, autophagy, in loss of cardiac myocytes. Autophagic cell death has been recently documented in myocardial cells from hypertrophied, failing, and hibernating myocardium. CONCLUSION In this review, we will list the basic mechanisms of apoptosis and autophagic cell death and examine the recent developments in apoptosis and autophagic cell death as it pertains to cardiovascular disease.
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Affiliation(s)
- Sanjay Kunapuli
- Division of Cardiology, Cedars Sinai Medical Center, Los Angeles and the University of California, Los Angeles, California 90048, USA
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38
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Ryabov VV, Krylov AL, Poponina YS, Maslov LN. Cardiac contractility after transplantation of autologous mononuclear bone marrow cells in patients with myocardial infarction. Bull Exp Biol Med 2006; 141:124-8. [PMID: 16929983 DOI: 10.1007/s10517-006-0111-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Autologous bone marrow mononuclear cells were transplanted by intracoronary infusion to patients with myocardial infarction after recovery of coronary perfusion. Controls received traditional therapy alone. Echocardiography was carried out before and 3 and 6 months after cell therapy. Cell transplantation did not appreciably improved left-ventricular contractility in comparison with the control group. In none patient cell therapy provoked malignant ventricular arrhythmias. Intracoronary infusion of bone marrow mononuclear cells in patients with myocardial infarction did not improve cardiac contractility and did not aggravate the course of the disease.
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Affiliation(s)
- V V Ryabov
- Institute of Cardiology, Tomsk Research Center, Siberian Division of Russian Academy of Medical Sciences
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39
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Quaini F, Urbanek K, Graiani G, Lagrasta C, Maestri R, Monica M, Boni A, Ferraro F, Delsignore R, Tasca G, Leri A, Kajstura J, Quaini E, Anversa P. The regenerative potential of the human heart. Int J Cardiol 2004; 95 Suppl 1:S26-8. [PMID: 15336841 DOI: 10.1016/s0167-5273(04)90008-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- F Quaini
- Department of Medicine and Pathology, University of Parma, Italy.
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Abstract
Adult ventricular myocytes can undergo mitotic division, resulting in an increase in the aggregate number of cells in the heart. The improvement in the methodological approach to the analysis of tissue sections by immunostaining and confocal microscopy has defeated the dogma that myocyte regeneration cannot occur in the adult heart. Most importantly, primitive and progenitor cells have been identified in the human heart. These cells express telomerase and have the capability of undergoing lineage commitment and rapid cell division, expanding significantly the contracting ventricular myocardium. These cell populations possess all the molecular components regulating the entry and progression through the cell cycle, karyokinesis, and cytokinesis. The recognition that myocyte hypertrophy and regeneration, as well as myocyte necrosis and apoptosis, occur in cardiac diseases has contributed to enhancing our understanding of the plasticity of the human heart.
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Affiliation(s)
- Jan Kajstura
- New York Medical College, Valhalla, NY 10595, USA
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41
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Abstract
The phenomenon of regeneration is of growing interest to medical researchers. Until recently this was an area in which research in flatworms and newts predominated, but there is now a proliferation of research concerning regeneration in virtually all of the organs, not only the heart. One of the object is restoration of function to a failing heart through cell transplantation, and there have been many reports seeking donor sources of somatic stem cells, i.e.: stem cells in marrow or skeletal muscle and ES cells, beginning with those in embryonic myocardial cell transplant experiments. In particular, reports of mesenchymal stem cell differentiation into nerve cell, myocardial cell, skeletal muscle cell, and vascular endothelial cell series have drawn attention to cell plasticity, and clinical applications are awaited.
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Affiliation(s)
- Satoshi Gojo
- Department of Cardiovascular Surgery, Saitama Medical Center, Kawagoe, Japan.
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42
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Abstract
The current treatment for heart failure is inadequate for a large number of patients who do not qualify for heart transplantation or innovative surgical therapy. Cellular augmentation of damaged myocardium has been actively investigated in the past decade. Cells best suited for the task are skeletal myoblasts and bone morrow mesenchymal stem cells. Both cell types are autologous, abundant, and easy to harvest. The focus of early human trials will be to establish the safety of an effective cellular dose. Trials conducted with an inadequate cellular dose may discredit cell therapy because of lack of effect but, more importantly, may provide a false sense of safety because of a lack of adverse events secondary to a small inoculating dose.
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Affiliation(s)
- Osman O Al-Radi
- Division of Cardiac Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
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Engel FB, Hauck L, Boehm M, Nabel EG, Dietz R, von Harsdorf R. p21(CIP1) Controls proliferating cell nuclear antigen level in adult cardiomyocytes. Mol Cell Biol 2003; 23:555-65. [PMID: 12509454 PMCID: PMC151523 DOI: 10.1128/mcb.23.2.555-565.2003] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Cell cycle withdrawal associated with terminal differentiation is responsible for the incapability of many organs to regenerate after injury. Here, we employed a cell-free system to analyze the molecular mechanisms underlying cell cycle arrest in cardiomyocytes. In this assay, incubation of S phase nuclei mixed with cytoplasmic extract of S phase cells and adult primary cardiomyocytes results in a dramatic reduction of proliferating cell nuclear antigen (PCNA) protein levels. This effect was blocked by the proteasome inhibitors MG132 and lactacystin, whereas actinomycin D and cycloheximide had no effect. Immunodepletion and addback experiments revealed that the effect of cardiomyocyte extract on PCNA protein levels is maintained by p21 but not p27. In serum-stimulated cardiomyocytes PCNA expression was reconstituted, whereas the protein level of p21 but not that of p27 was reduced. Cytoplasmic extract of serum-stimulated cardiomyocytes did not influence the PCNA protein level in S phase nuclei. Moreover, the hypertrophic effect of serum stimulation was blocked by ectopic expression of p21 and the PCNA protein level was found to be upregulated in adult cardiomyocytes derived from p21 knockout mice. Our data provide evidence that p21 regulates the PCNA protein level in adult cardiomyocytes, which has implications for cardiomyocyte growth control.
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Affiliation(s)
- Felix B Engel
- Department of Cardiology, Campus Virchow Clinic, Charité, Humboldt University, Max Delbrück Center for Molecular Medicine, Berlin, Germany
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44
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45
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Arnaiz MR, Fichera LE, Postan M. Cardiac myocyte hypertrophy and proliferating cell nuclear antigen expression in Wistar rats infected with Trypanosoma cruzi. J Parasitol 2002; 88:919-25. [PMID: 12435130 DOI: 10.1645/0022-3395(2002)088[0919:cmhapc]2.0.co;2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Chagasic cardiomyopathy is a major life-threatening complication of Trypanosoma cruzi infection in human beings. This study focuses on the hypertrophic and hyperplastic mechanisms underlying the structural changes of the heart during experimental infection. Proliferating cell nuclear antigen (PCNA) expression, transversal diameter, nuclear area, and number of nuclei per unit volume were determined in the ventricular myocytes of T. cruzi-infected Wistar rats. PCNA expression was enhanced throughout the inflamed myocardium and in the spared areas of the left ventricular wall and the septum. Myocyte width increased from 26 to 75% at the inflammation-free myocardium (P < 0.0001), whereas it decreased 25% at the inflamed left ventricular wall areas (P < 0.001). Nuclear size increased in the inflammation-free myocardium of the left ventricle and the septum (> 10-36%, P < 0.01 and >0.2-32%, P < 0.03, respectively) and decreased at the inflamed areas of the left ventricular wall (10-22%. P < 0.02) with respect to the controls. The number of nuclei per unit volume decreased at the inflamed myocardium regardless of topographical location (36-65%) with respect to the controls (P < 0.0001) and in the inflammation-free myocardium of the right ventricle and the septum (<21-37%, P < 0.002 and <8-39%, P < 0.002, respectively). These results show that the heart responds to T. cruzi infection with DNA repair and cell multiplication in the inflamed sites and with hypertrophy of the unaffected myocardium.
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Affiliation(s)
- María Rosa Arnaiz
- Instituto Nacional de Parasitología Dr. Mario Fatala Chaben/ANLIS and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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46
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Poole-Wilson PA. Death or repair of the myocyte in chronic heart failure**Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. J Am Coll Cardiol 2002. [DOI: 10.1016/s0735-1097(02)02112-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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47
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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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48
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Regula KM, Kirshenbaum LA. p53 activates the mitochondrial death pathway and apoptosis of ventricular myocytes independent of de novo gene transcription. J Mol Cell Cardiol 2001; 33:1435-45. [PMID: 11448132 DOI: 10.1006/jmcc.2001.1405] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The tumor suppressor p53 is known to regulate gene transcription and apoptosis in mammalian cells. In the present study we ascertain whether these events are mutually dependent and obligatorily linked for induction of apoptosis of ventricular myocytes. Adenovirus mediated gene delivery of wild p53 (p53WT) or a mutant form of p53 (p53MT) defective for gene transcription to ventricular myocytes was confirmed by Western blot analysis. A significant increase in the p53 dependent genes Bax and MDM2 was observed with p53WT but not p53MT. Nuclear DNA visualized by agarose gel electrophoresis revealed nucleosomal DNA laddering in the presence of either p53 protein. Apoptosis was substantiated by Hoechst 33258 nuclear staining. Perturbations to mitochondria consistent with the mitochondrial death pathway, including loss of mitochondrial transmembrane potential Delta(psi)m and cytochrome c release were observed with p53WT and p53MT. An increase in caspase 3-like activity was noted with either p53WT or p53MT protein that was suppressed by the caspase 3 inhibitor Ac-DEVD-CHO. To our knowledge the experiments described here provide the first indication that p53 activates the mitochondrial death pathway and provokes apoptosis of ventricular myocytes independent of DNA binding and de novo gene activation.
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Affiliation(s)
- K M Regula
- Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, Winnipeg, Manitoba, R2H 2A6, Canada
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49
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Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001; 344:1750-7. [PMID: 11396441 DOI: 10.1056/nejm200106073442303] [Citation(s) in RCA: 917] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND The scarring of the heart that results from myocardial infarction has been interpreted as evidence that the heart is composed of myocytes that are unable to divide. However, recent observations have provided evidence of proliferation of myocytes in the adult heart. Therefore, we studied the extent of mitosis among myocytes after myocardial infarction in humans. METHODS Samples from the border of the infarct and from areas of the myocardium distant from the infarct were obtained from 13 patients who had died 4 to 12 days after infarction. Ten normal hearts were used as controls. Myocytes that had entered the cell cycle in preparation for cell division were measured by labeling of the nuclear antigen Ki-67, which is associated with cell division. The fraction of myocyte nuclei that were undergoing mitosis was determined, and the mitotic index (the ratio of the number of nuclei undergoing mitosis to the number not undergoing mitosis) was calculated. The presence of mitotic spindles, contractile rings, karyokinesis, and cytokinesis was also recorded. RESULTS In the infarcted hearts, Ki-67 expression was detected in 4 percent of myocyte nuclei in the regions adjacent to the infarcts and in 1 percent of those in regions distant from the infarcts. The reentry of myocytes into the cell cycle resulted in mitotic indexes of 0.08 percent and 0.03 percent, respectively, in the zones adjacent to and distant from the infarcts. Events characteristic of cell division--the formation of the mitotic spindles, the formation of contractile rings, karyokinesis, and cytokinesis--were identified; these features demonstrated that there was myocyte proliferation after myocardial infarction. CONCLUSIONS Our results challenge the dogma that the adult heart is a postmitotic organ and indicate that the regeneration of myocytes may be a critical component of the increase in muscle mass of the myocardium.
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Affiliation(s)
- A P Beltrami
- Department of Medicine, New York Medical College, Valhalla 10595, USA
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50
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Abstract
Heart failure is a changing paradigm. The hemodynamic model, which served our needs well from the 1950s through the early 1980s, has now been largely abandoned, except for the management of decompensated patients in the hospital. The pathophysiology is exceedingly complex and involves structural changes, such as loss of myofilaments, apoptosis and disorganization of the cytoskeleton, as well as disturbances in Ca(2+) homeostasis, alteration in receptor density, signal transduction, and collagen synthesis. A more contemporary working hypothesis is that heart failure is a progressive disorder of left ventricular remodeling, usually resulting from an index event, that culminates in a clinical syndrome characterized by impaired cardiac function and circulatory congestion. This change in the framework of our understanding of the pathophysiology of heart failure is predicated on the results of numerous clinical trials conducted during the past 20 years. New therapies are now evolving that are designed to inhibit neuroendocrine and cytokine activation, whereas drugs specifically designed to heighten cardiac contractility and "unload" the left ventricle have proven to be unhelpful in long-term management of patients with chronic heart failure. However, the hemodynamic model is still relevant for patients in the hospital with decompensated heart failure, where positive inotropic drugs and vasodilators are still widely used. The modern treatment of chronic heart failure is now largely based on the neurohormonal hypothesis, which states that neuroendocrine activation is important in the progression of heart failure and that inhibition of neurohormones is likely to have long-term benefit with regard to morbidity and mortality. Thus, the evolution of treatment for chronic heart failure as a result of clinical trials has provided much enlightenment for our understanding of the fundamental biology of the disorder, a reversal of the usual flow of information from basic science to clinical investigation.
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Affiliation(s)
- G S Francis
- George M. and Linda H. Kaufman Center for Heart Failure, Department of Cardiology, The Cleveland Clinic Foundation, OH 44195, USA
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