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Telomeres and Telomerase in Heart Ontogenesis, Aging and Regeneration

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Telomeres and Telomerase in Heart Ontogenesis, Aging and Regeneration cells Review Telomeres and Telomerase in Heart Ontogenesis, Aging and Regeneration Denis Nalobin 1,* , Svetlana Alipkina 1, Anna Gaidamaka 1, Alexander Glukhov 1,2 and Zaza Khuchua 2,3,4 1 Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russian; [email protected] (S.A.); [email protected] (A.G.); [email protected] (A.G.) 2 Department of Biochemistry, Sechenov First Moscow State Medical University, 119991 Moscow, Russian; [email protected] 3 Institute of Chemical Biology Ilia State University, 0162 Tbilisi, Georgia 4 Division of Molecular and Cardiovascular Biology, Cincinnati Children’s Medical Center, Cincinnati, OH 45229, USA * Correspondence: [email protected]; Tel.: +7-916-939-0990 Received: 30 November 2019; Accepted: 14 February 2020; Published: 22 February 2020 Abstract: The main purpose of the review article is to assess the contributions of telomere length and telomerase activity to the cardiac function at different stages of development and clarify their role in cardiac disorders. It has been shown that the telomerase complex and telomeres are of great importance in many periods of ontogenesis due to the regulation of the proliferative capacity of heart cells. The review article also discusses the problems of heart regeneration and the identification of possible causes of dysfunction of telomeres and telomerase. Keywords: cardiomyocytes; telomere length; telomerase activity; development; regeneration; reactive oxygen species 1. Introduction The cardiovascular system plays a vital for the whole organism. It performs many vital functions such as supplying organs and tissues with nutrients, hormones, carrying oxygen to the cells and maintaining physiological temperature. According to the World Health Organization, diseases of the cardiovascular system are the main cause of lethality worldwide. Every year, more than 7.4 million people die from coronary heart disease worldwide, and these rates continue to grow. Congenital heart defects are also highly prevalent and may be a cause of serious complications in the future. Thus, the search for solutions to the cause and consequences of heart diseases is one of the most serious biomedical problems. The possibility to regenerate the mammalian heart is still rarely studied; however, studying it would allow finding new ways to restore the heart after severe injuries. A huge number of factors affect the functioning of the heart. One of them is cell aging, which manifests itself in the form of various disorders. Cellular aging is associated to a greater extent with the loss of telomere length and a decrease in telomerase activity. Understanding the processes of regulation of telomere length and telomerase activity in the ontogenesis of cardiac tissue can help to understand the causes of heart disease in one or another period of development of the organism. Cells 2020, 9, 503; doi:10.3390/cells9020503 www.mdpi.com/journal/cells Cells 2020, 9, 503 2 of 12 Cells 2020, 8, x 2 of 11 2.2. TelomeresTelomeres andand TelomereTelomere Complex Complex InIn 1961,1961, LeonardLeonard HayflickHayflick discovereddiscovered thethe limitlimit ofof somaticsomatic cellcell divisiondivision inin vitrovitro.. TheThe limitlimit isis namednamed afterafter the the scientist—the scientist— Hayflickthe Hayflick limit. limit. According According to Hayflick’s to Hayflick’s observations, observation human fibroblastss, human dividingfibroblasts in dividing a cell culture in a cell died culture after died approximately after approximately 50 divisions. 50 divisions. The cells The showed cells showed signs of signs aging, of stoppedaging, stopped dividing dividing and underwent and underwent programmed programmed cell death cell [ 1death]. [1]. TenTen yearsyears afterafter thethe discoverydiscovery ofof thethe HayflickHayflick limit,limit, OlovnikovOlovnikov hypothesizedhypothesized thatthat DNADNA polymerasepolymerase cannotcannot copycopy aa smallsmall regionregion atat thethe endend ofof chromosome (telomere),(telomere), whichwhich leadsleads toto terminalterminal under-replicationunder-replication ofof DNADNA [[22]] (Figure(Figure1 ).1). FigureFigure 1.1. Problems associated with chromosomes’chromosomes’ terminalterminal under-replicationunder-replication [[2].2]. ScientistsScientists postulatedpostulated that that telomeres telomeres undergo undergo shortening shortening with with each each cell cell division division and and assumed assumed that thisthat phenomenonthis phenomenon was associatedwas associated with thewith cell the division cell division limit. limit. This hypothesisThis hypothesis was confirmed was confirmed in 1985, in when1985, when Greider Greider and Blackburn and Blackburn (1985) (1985) identified identified an enzyme an enzyme in the in ciliate the ciliateTetrahymena Tetrahymena thermophila thermophilathat preventedthat prevent theed degradation the degradation of the of ends the ends of chromosomes. of chromosomes. The enzymeThe enzyme was namedwas named telomerase telomerase [2]. [2]. VertebrateVertebrate telomerestelomeres consistconsist ofof repeatingrepeating TTAGGGTTAGGG sequencessequences atat thethe endsends ofof chromosomeschromosomes andand maintainmaintain theirtheir integrity.integrity. SinceSince DNADNA replicationreplication isis asymmetricasymmetric atat bothboth strands,strands, thethe sequencesequence atat thethe 33′0 endend wouldwould loselose 30–20030–200 nucleotidesnucleotides withwith eacheach cyclecycle ofof DNADNA replicationreplication andand cellcell division.division. TelomeresTelomeres havehave non-codingnon-coding recurringrecurring sequencessequences atat thethe 33′0 endend toto preventprevent thethe lossloss ofof codingcoding sequencessequences duringduring replicationreplication [[33].]. Moreover, telomeres are covered withwith ShelterinShelterin complex consisting of sixsix proteins:proteins: TRF1TRF1 (telomere(telomere repeat repeat binding binding factor factor 1), TRF2 1), TRF2 (telomere (telomere repeat repeat binding binding factor 2), factor TIN2 (TRF1-interacted2), TIN2 (TRF1- nuclearinteracted protein nuclear 2), RAP1protein (rif-associated 2), RAP1 (rif-associated protein), POT1 protein), (protection POT1 (p ofrotection telomeres) of telomeres) and TPP1 (telomereand TPP1 protected(telomere proteinprotected 1). protein Telomeres 1). Telomeres end with end a single-strandedwith a single-stranded 30-end, 3′ which-end, which has a has compact a compact T-loop T- structureloop structure that maintains that maintains their stabilitytheir stability [4]. Telomeres [4]. Telomeres were were proposed proposed as mitotic as mitotic clocks clocks that show that show how manyhow many times times a cell a has cell divided has divided [5]. [5]. WhenWhen telomerestelomeres shortenshorten toto aa criticalcritical length,length, thethe cellcell goesgoes intointo aa state of senescence,senescence, which initiates aa seriesseries ofof changeschanges inin genegene expressionexpression patternspatterns ofof cellcell cyclecycle inhibitors,inhibitors, decreasesdecreases cellularcellular proliferativeproliferative potentialpotential andand activatesactivates apoptosisapoptosis [[66].]. TelomeraseTelomerase is is responsible responsible for for telomere telomere elongation elongation and and consists consists of anof RNAan RNA component component (TERC) (TERC) and telomeraseand telomerase reverse reverse transcriptase transcriptase (TERT), (TERT), a catalytic a catalytic component. component. TERT TERT uses uses TERC TERC as a as template a template for synthesizingfor synthesizing new new repeats repeats of telomericof telomeric DNA DNA at at the the single-stranded single-stranded ends ends of of chromosomes chromosomes [ 7[7].]. MostMost somaticsomatic cellscells lack lack telomerase telomerase activity, activity, but undi butff erentiatedundifferentiated germ cells, germ stem cells, cells, activatedstem cells, lymphocytes activated andlymphocytes most tumor and cells most have tumor a high cells level have of telomerasea high level activity of telomerase to overcome activity telomere to overcome contraction telomere and maintaincontraction limitless and maintain cell division. limitless However, cell division. differentiated However, resting differentiated cells usually resting have a lowcells or usually undetectable have a levellow or of undetectable telomerase activity level of [8 telomerase]. activity [8]. Cells 2020, 9, 503 3 of 12 3. Embryonic Development of the Heart The heart begins to function in the early stages of development in both mammals and lower vertebrates such as Danio rerio (zebrafish) [9,10]. In mice, the level of proliferation of cardiomyocytes (CM) is high in early embryogenesis, and then it gradually decreases until the 10th to 12th day of embryonic development (E10–12) when the heart is almost fully formed [9,11]. Similar dynamics are also shown for telomerase: its activity is detected in the heart tissue of the human fetus until the 12th week of embryonic development, which coincides with the histological differentiation of the myoblasts of the heart into cardiomyocytes [12]. This observation is consistent with the fact that, by the sixth month of prenatal development, the morphological appearance of the heart muscle is almost the same as that of an adult [12]. However, a full picture of dynamics of telomerase activity during the cardiac embryonic development is still unclear. It is known that activity is registered during E11.5 [13] and E16.5 in mice [14], as well as on E10 and E20 in rats. Moreover,
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