DNA Damage Response Mediates Pressure Overload–Induced Cardiomyocyte Hypertrophy
2019; Lippincott Williams & Wilkins; Volume: 139; Issue: 9 Linguagem: Inglês
10.1161/circulationaha.118.034822
ISSN1524-4539
AutoresYuji Nakada, Ngoc Uyen Nhi Nguyen, Feng Xiao, Jainy Savla, Nicholas T. Lam, Salim Abdisalaam, Souparno Bhattacharya, Shibani Mukherjee, Aroumougame Asaithamby, Thomas G. Gillette, Joseph A. Hill, Hesham A. Sadek,
Tópico(s)Genetics, Aging, and Longevity in Model Organisms
ResumoHomeCirculationVol. 139, No. 9DNA Damage Response Mediates Pressure Overload–Induced Cardiomyocyte Hypertrophy Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBDNA Damage Response Mediates Pressure Overload–Induced Cardiomyocyte Hypertrophy Yuji Nakada, PhD, Ngoc Uyen Nhi Nguyen, PhD, Feng Xiao, PhD, Jainy J. Savla, MD, Nicholas T. Lam, PhD, Salim Abdisalaam, PhD, Souparno Bhattacharya, PhD, Shibani Mukherjee, PhD, Aroumougame Asaithamby, PhD, Thomas G. Gillette, PhD, Joseph A. Hill, MD, PhD and Hesham A. Sadek, MD, PhD Yuji NakadaYuji Nakada Department of Internal Medicine (Y.N., N.U.N.N., F.X., J.J.S., N.T.L., T.G.G., J.A.H., H.A.S.), the University of Texas Southwestern Medical Center, Dallas. , Ngoc Uyen Nhi NguyenNgoc Uyen Nhi Nguyen Department of Internal Medicine (Y.N., N.U.N.N., F.X., J.J.S., N.T.L., T.G.G., J.A.H., H.A.S.), the University of Texas Southwestern Medical Center, Dallas. , Feng XiaoFeng Xiao Department of Internal Medicine (Y.N., N.U.N.N., F.X., J.J.S., N.T.L., T.G.G., J.A.H., H.A.S.), the University of Texas Southwestern Medical Center, Dallas. , Jainy J. SavlaJainy J. Savla Department of Internal Medicine (Y.N., N.U.N.N., F.X., J.J.S., N.T.L., T.G.G., J.A.H., H.A.S.), the University of Texas Southwestern Medical Center, Dallas. , Nicholas T. LamNicholas T. Lam Department of Internal Medicine (Y.N., N.U.N.N., F.X., J.J.S., N.T.L., T.G.G., J.A.H., H.A.S.), the University of Texas Southwestern Medical Center, Dallas. , Salim AbdisalaamSalim Abdisalaam Department of Radiation Oncology (S.A., S.B., S.M., A.A.), the University of Texas Southwestern Medical Center, Dallas. , Souparno BhattacharyaSouparno Bhattacharya Department of Radiation Oncology (S.A., S.B., S.M., A.A.), the University of Texas Southwestern Medical Center, Dallas. , Shibani MukherjeeShibani Mukherjee Department of Radiation Oncology (S.A., S.B., S.M., A.A.), the University of Texas Southwestern Medical Center, Dallas. , Aroumougame AsaithambyAroumougame Asaithamby Department of Radiation Oncology (S.A., S.B., S.M., A.A.), the University of Texas Southwestern Medical Center, Dallas. , Thomas G. GilletteThomas G. Gillette Department of Internal Medicine (Y.N., N.U.N.N., F.X., J.J.S., N.T.L., T.G.G., J.A.H., H.A.S.), the University of Texas Southwestern Medical Center, Dallas. , Joseph A. HillJoseph A. Hill Department of Internal Medicine (Y.N., N.U.N.N., F.X., J.J.S., N.T.L., T.G.G., J.A.H., H.A.S.), the University of Texas Southwestern Medical Center, Dallas. Center for Regenerative Science and Medicine (J.A.H., H.A.S.), the University of Texas Southwestern Medical Center, Dallas. and Hesham A. SadekHesham A. Sadek Hesham A. Sadek, MD, PhD, Department of Internal Medicine, Division of Cardiology, Department of Molecular Biology, and Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX, 75390. Email E-mail Address: [email protected] Department of Internal Medicine (Y.N., N.U.N.N., F.X., J.J.S., N.T.L., T.G.G., J.A.H., H.A.S.), the University of Texas Southwestern Medical Center, Dallas. Center for Regenerative Science and Medicine (J.A.H., H.A.S.), the University of Texas Southwestern Medical Center, Dallas. Originally published25 Feb 2019https://doi.org/10.1161/CIRCULATIONAHA.118.034822Circulation. 2019;139:1237–1239Cardiac hypertrophy is a common physiological response to cardiac stress that is characterized by increased thickness of the heart muscle. Maladaptive cardiac hypertrophy is often associated with diseases such as hypertension, valvular disease, and ischemic heart disease, all of which can result in heart failure. Despite the large body of literature outlining mechanisms of cardiac hypertrophy, novel mechanisms continue to be identified, highlighting the complexity of this phenotype.For a brief period of time after birth, mammalian cardiomyocytes possess the capacity to recover heart function after substantial cardiac injury through proliferation of preexisting cardiomyocytes, after which most cardiomyocytes permanently exit the cell cycle, and cardiac growth occurs through hypertrophy rather than hyperplasia. Our group previously showed that DNA damage response (DDR) is an important mediator of postnatal cell cycle arrest in cardiomyocytes. However, whether DDR also regulates hypertrophic growth of cardiomyocytes remains unknown.1Therefore, we conducted the current study to examine the role of DDR in regulation of cardiomyocyte hypertrophy in response to pressure overload. First, we used Ang II (angiotensin II)–infused mice as a model for pressure overload–induced cardiomyocyte hypertrophy. All animal studies were conducted according to institutional guidelines following approval of the corresponding animal protocols. Infusion of Ang II for 2 weeks (Angiotensin II, Sigma; 1000 ng/kg/min, alzet osmotic pump) in adult C57/B6 mice caused cardiac hypertrophy and significantly induced DNA double-strand breaks (DSBs) as indicated by increased γ-H2AX (phosphorylated histone H2AX [Ser139]) foci. This resulted in a significant increase in the number of phosphorylated ATM (ataxia telangiectasia mutated; Ser1987) foci, a primary kinase in the DDR pathway (Figure, A, top left and middle). Similar findings were observed in a second mouse model of pressure overload achieved through transverse aortic constriction (Figure, A, bottom left and middle). Importantly, we found that transverse aortic constriction resulted in a marked increase in phosphorylated pDNA-PKcs (Thr2609; DNA-dependent protein kinase, catalytic subunit) in cardiomyocyte nuclei (Figure, A, right). While activation of ATM can occur in a variety of types of DNA damage, activation of DNA-PKcs is specifically induced by DSBs.2 These results indicate that pressure overload induces DSBs in cardiomyocytes.Download figureDownload PowerPointFigure. Inhibition of ATM (ataxia telangiectasia mutated) kinase signaling inhibits pressure overload–induced cardiomyocyte hypertrophy. A, Left, Representative confocal images with anti-γ-H2AX (anti-phosphorylated histone H2AX [Ser139]) and anti-cardiac troponin T antibodies show significantly increased number of γ-H2AX foci in Ang II (angiotensin II) cardiomyocyte nuclei. Middle, Representative confocal images with anti-pATM (anti-phosphorylated ATM) and anti-a-actinin antibodies show a significantly increased number of pATM foci in Ang II cardiomyocyte nuclei. Right, Representative confocal images with anti-pDNA-PKcs (Thr2609; phosphorylated DNA-dependent protein kinase, catalytic subunit) and anti-a-actinin antibodies show a significantly increased number of pDNA-PKcs foci in transverse aortic constriction (TAC) cardiomyocyte nuclei. Each graph shows the quantification of γ-H2AX, pATM, and pDNA-PKcs foci in cardiomyocyte nuclei in both Ang ll mice and TAC-operated mice (15 cells were quantified each, n=3 each). B, KU60019-injected Ang II mice show lower heart weight to tibial length ratio and smaller cardiomyocyte size as assessed by wheat germ agglutinin (WGA) staining compared to dimethyl sulfoxide (DMSO)–injected Ang II mice (2-month-old male C57/B6J, n=3 each). C, KU60019-injected TAC-operated mice show a lower heart weight to tibial length ratio and smaller cardiomyocyte size as assessed by WGA staining comparison with DMSO-injected TAC-operated mice (2-month-old male C57/B6J, n=3 each). D, ATM KO (knockout) mice have a lower heart weight to tibial length ratio and smaller cardiomyocyte size compared with control mice after 3 weeks of TAC operation (2-month-old males, n=8 for sham, n=6 for aMHC-MerCreMer, n=8 for aMHC-MerCreMer;ATMf/f). E, Western blot and quantitative analysis show a greater reduction in markers of cardiac hypertrophy in the ATM KO than in control (n=3 each). GAPDH is used to normalize sample loading. F, Expression of Cain is significantly increased in the ATM KO with TAC by immunostaining images of anti-Cain antibody. G, Schematic of the suggested signaling pathway. Activated ATM caused by DNA double strand breaks (DSBs) accelerates degradation of Cain resulting in calcineurin activation. ATM also phosphorylates 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1, also known as Phas-1) to promote dissociation of the 4E-BP1/eIF-4E (eukaryotic translation initiation factor 4E) complex. Free eIF-4E initiates translation and increases protein synthesis. Scale bars represent 10 μm for low-magnification views and 5 μm for high-magnification views in A;1 mm for hematoxylin and eosin staining and 50 μm for WGA staining in B, C, and D; and 10 μm in F. Data are presented as mean±SEM. Student t test was used to determine statistical significance. *P<0.05, **P<0.01. AKT indicates AKT serine/threonine kinase 1; DAPI, 4',6-diamidino-2-phenylindole, dihydrochloride; Erk1/2, mitogen-activated protein kinase; pAKT, phosphorylated AKT serine/threonine kinase 1; and pErk1/2, phosphorylated mitogen-activated protein kinase.To examine whether DDR mediates cardiomyocyte hypertrophy, we performed daily injections of KU60019 (20 mg/kg/d), a selective inhibitor of the ATM kinase, during Ang II infusion for 2 weeks. This resulted in a significant decrease in cardiac mass, and cardiomyocyte size in the treated group compared with the control group (Figure, B). Similar results were also obtained using KU60019 in a transverse aortic constriction model of pressure overload–induced hypertrophy (Figure, C).In addition, to examine whether genetic deletion of ATM in cardiomyocytes similarly inhibits pressure overload–induced cardiomyocyte hypertrophy, we generated a cardiomyocyte-specific, conditional ATM KO (knockout) mouse. ATM KO (aMHC-MerCreMer;ATMf/f) was produced by crossbreeding between A1cfTg(Myh6-Cre/Esr1*)1Jmk/J (aMHC-MerCreMer) and ATMtm2.1Fwa/J (ATMf/f), obtained from the Jackson Laboratory. Similar to the previous results with pharmacological ATM inhibition, we found that the genetic deletion of ATM prevented transverse aortic constriction–induced cardiomyocyte hypertrophy (Figure, D).Quantitative analysis of cardiac hypertrophy pathways by Western blot showed a significant reduction of both calcineurin and Rcan 1.4 (a marker of calcineurin activation) levels in the ATM KO hearts. We also found that the abundance of phosphorylated 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1, also known as Phas-1) was significantly decreased in the ATM KO hearts. Phosphorylation of 4E-BP1 (an inhibitor of mRNA translation) results in its inhibition and induction of cardiomyocyte hypertrophy (Figure, E). We did not observe significant differences in other hypertrophy pathways tested (Figure, E). Interestingly, we also found that the abundance of Cain, a calcineurin inhibitor protein, was significantly increased in the ATM KO hearts (Figure, F).To further examine how ATM regulates Cain and 4E-BP1, we explored whether they include conserved SCD (S/T-Q cluster domains) domains, which are putative targets for ATM. Intriguingly, we found that both Cain and 4E-BP1 have been previously shown to be direct targets of ATM.3,4 While our results implicate calcineurin and 4E-BP1 as mediators of cardiomyocyte hypertrophy downstream of ATM, there may be other ATM and DDR targets involved in regulation of cardiomyocyte hypertrophy after DNA damage (Figure, G).It is important to note that while a recent elegant study showed that DNA single strand breaks occur during pressure overload–induced cardiomyocyte hypertrophy and heart failure, the investigators reported no induction of DSBs. This discrepancy may have occurred due to the lower sensitivity of COMET assays used in that study for detection of DSBs.5 As outlined earlier, the combination of ATM and DNA-PKcs activation in cardiomyocytes, as we report here, is indicative of DSBs. Collectively, there is a growing body of evidence suggesting that DDR is an important regulator of both physiological and pathological cardiomyocyte growth.In summary, we demonstrate that pressure overload induces DNA DSBs in cardiomyocytes, resulting in activation of ATM. Importantly, our results suggest that disruption of DDR through pharmacological or genetic loss of ATM function can modulate pressure overload–induced cardiomyocyte hypertrophy.Sources of FundingDr Sadek is supported by grants from the National Institutes of Health (1R01HL115275 and 5R01H2131778), National Aeronautics and Space Administration (NNX-15AE06G), American Heart Association (16EIA27740034), Cancer Prevention and Research Institute of Texas (RP160520), Hamon Center for Regenerative Science and Medicine, and Fondation Leducq. Dr Asaithamby is supported by a grant from the National Institute of Aging (R01AG053341). Dr Hill is supported by grants from the Nattional Institute of Health (R01120732, R01128215, and R01126012).DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circData sharing: Data, analytic methods, and study materials available to other researchers through direct communication upon request.Guest Editor for this article was Mauro Giacca, MD, PhD.Hesham A. Sadek, MD, PhD, Department of Internal Medicine, Division of Cardiology, Department of Molecular Biology, and Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX, 75390. Email hesham.[email protected]eduReferences1. Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, Grinsfelder D, Rothermel BA, Chen R, Garcia JA, Santos CX, Thet S, Mori E, Kinter MT, Rindler PM, Zacchigna S, Mukherjee S, Chen DJ, Mahmoud AI, Giacca M, Rabinovitch PS, Aroumougame A, Shah AM, Szweda LI, Sadek HA. 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February 26, 2019Vol 139, Issue 9 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.034822PMID: 30802166 Originally publishedFebruary 25, 2019 KeywordsDNA, double-strandedmyocytes, cardiacataxia telangiectasia, mutatedKU60019angiotensin IIDNA damagehypertrophyPDF download Advertisement SubjectsBasic Science ResearchMechanismsMyocardial Biology
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