An Energy-Sensor Network Takes Center Stage During Endothelial Aging

Abstract

HomeCirculation ResearchVol. 106, No. 8An Energy-Sensor Network Takes Center Stage During Endothelial Aging Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAn Energy-Sensor Network Takes Center Stage During Endothelial Aging Michael Potente Michael PotenteMichael Potente From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine; and Department of Cardiology, Internal Medicine III, Goethe University, Frankfurt, Germany. Search for more papers by this author Originally published30 Apr 2010https://doi.org/10.1161/CIRCRESAHA.110.219352Circulation Research. 2010;106:1316–1318Blood vessels form a critical interface between the environment and the organism by supplying nutrients, oxygen and macromolecules to all tissues and cells in the body. Endothelial cells (ECs) line the inner surface of the hierarchically branched blood vessel network and integrate functionally into different organs to support tissue growth and function in development, physiology, and disease. In healthy postnatal tissues, ECs are mostly quiescent and rarely migrate or proliferate. However, ECs possess a remarkable phenotypic plasticity in terms of being able to proliferate rapidly in response to vascular injury, tissue ischemia, or other stress conditions. This phenotypic plasticity progressively declines when ECs age and/or are permanently exposed to metabolic (eg, hyperglycemia) and environmental stressors (eg, oxidative stress) and coincides with the development of endothelial senescence.1 Cellular senescence is a stress response that is characterized by a robust inhibition of cell proliferation, which often becomes irreversible and independent of the initial stress signal.2 Senescence can be observed in most mammalian cells after extended propagation in culture and is related to the attrition of telomeres after repetitive cycles of cell divisions.2 In addition to telomere shortening, other stressors such as DNA damage, genomic instability, and oxidative stress can induce a similar growth arrest and trigger senescence.2 Senescent cells display characteristic alterations in cell morphology and gene expression that may weaken cellular functions. In ECs, these changes cause a phenotype that is proinflammatory, prothrombotic, and proatherosclerotic, which also negatively affects the vasodilatory, angiogenic, and regenerative properties of ECs and, thus, accelerates the development of several cardiovascular diseases.1 Despite advances in understanding the molecular mechanisms of endothelial senescence and vascular aging, the signaling networks governing the development and progression of EC senescence remain less well defined. In this issue of Circulation Research, a new report from Zu et al describe an intricate signaling mechanism whereby sirtuin (SIRT)1, a NAD+-dependent protein deacetylase that mediates adaptive responses to a variety of stresses, exerts its senescence protective effects on the vascular endothelium.3SIRT1 belongs to the family of sirtuins, which have gained considerable attention for their impact on several important physiological processes associated with metabolism, stress resistance, and aging (for a comprehensive overview on sirtuins, see elsewhere4,5). SIRT1 acts as a NAD+-dependent protein deacetylase that adjusts cellular responses to the energetic state of the cell. By deacetylating transcription factors, cofactors, and histones, SIRT1 has been shown to promote resistance to metabolic, hypoxic, and genotoxic stress, thereby controlling cell metabolism, survival, proliferation, and cell fate.4,5 More recent studies highlighted important homeostatic functions of SIRT1 in the vascular endothelium, where it modulates vascular growth, shape and function.6 Consistent with these findings, Zu et al report that SIRT1 prevents cell culture-induced EC senescence in vitro as well as stress-induced senescence in mice.3 Interestingly, the authors found that SIRT1 mRNA and protein levels progressively declined during the development of endothelial senescence, whereas the protein levels of the stress-responsive serine/threonine kinase LKB1 were inversely regulated and robustly increased. The enhanced expression of LKB1 was also associated with an increased activity of the downstream target of LKB1, AMP-activated protein kinase (AMPK), a sensor of cellular energy status and master regulator of metabolism. The authors further showed that signaling by LKB1 and AMPK retarded endothelial proliferation and accelerated endothelial senescence development.3 The concept that SIRT1 prevents endothelial senescence is not new. Indeed, previous studies showed that SIRT1 prevents hydrogen peroxide-induced premature senescence of ECs by deacetylating the tumor suppressor p53.7 Nevertheless, it is the first time that the antisenescent activity of SIRT1 has been linked to deregulated LKB1/AMPK signaling. The important role of the LKB1/AMPK pathway as a SIRT1 target is highlighted by results showing that LKB1- and AMPK-induced senescence of EC are prevented by increasing the levels of SIRT1. Conversely, knocking down SIRT1 in ECs induced endothelial senescence and elevated the protein levels of LKB1, as well the phosphorylation of AMPK at threonine 172,3 a site that marks activation of AMPK by LKB1.The finding that SIRT1 opposes signaling by the LKB1/AMPK pathway is perhaps the most unexpected finding by Zu et al, because previous studies in skeletal muscle cells have shown that AMPK enhances SIRT1 activity by elevating cellular NAD+ levels.8,9 Why should the LKB1/AMPK pathway boost its own inactivation through SIRT1? A possible explanation for such a negative-feedback loop might be that the signaling dynamics of the LKB1/AMPK pathway need to be balanced and that excessive activity is detrimental for ECs. Consistent with such model, Zu et al demonstrate that constitutive and prolonged LKB1/AMPK activation leads to an inhibition of EC proliferation and promotes endothelial senescence, whereas transient activation of LKB1/AMPK is known to protect cells against stress by maintaining energy homeostasis.10 These considerations suggest that SIRT1 acts as a fine-tuner of endothelial LKB1/AMPK signaling that ensures a signaling response that is temporally and quantitatively balanced and whose inactivation during aging will consequently promote EC senescence (Figure 1). Download figureDownload PowerPointFigure 1. Proposed model for the regulation of LKB1/AMPK signaling by SIRT1 in aging endothelial cells. In young ECs, activation of the LKB1/AMPK pathway leads to enhanced SIRT1 activity, which itself acts as a negative regulator of this pathway by promoting deacetylation and degradation of LKB1. This negative-feedback regulation prevents prolonged activation of the LKB1/AMPK signaling and, thereby, allows EC proliferation. During aging, endothelial SIRT1 mRNA expression is reduced through an unknown molecular mechanism, which results in derepression and prolonged activation of LKB1/AMPK signaling. The unregulated LKB1/AMPK pathway inhibits EC proliferation and promotes the development of senescence.How does SIRT1 antagonize LKB1 signaling? The authors provide evidence that LKB1 is an acetylated protein, which is targeted by SIRT1 for deacetylation and degradation, thereby downregulating LKB1 activity.3 The regulation of LKB1 by reversible acetylation adds this kinase to the growing list of signaling molecules, whose activity is regulated by acetylation. Acetylation synergizes or competes with other posttranslational modifications such as ubiquitylation, sumoylation, or methylation to alter protein activity, subcellular localization or stability.3 The findings by Zu et al suggest that deacetylation of LKB1 by SIRT1 leads to increased LKB1 ubiquitylation and proteasomal degradation.3 Because both acetylation and ubiquitylation occur on lysine residues, deacetylation of LKB1 by SIRT1 might control the accessibility of these residues for ubiquitylation and thereby alter its stability in ECs. In other cell lines, however, SIRT1-mediated deacetylation of LKB1 does not induce its degradation but instead increases its cytoplasmic localization and activity.11,12 How can these opposing findings be explained? Besides tissue-specific functions of SIRT1 and LKB1, differences in the acetylation pattern of LKB1 might be a plausible explanation. Lan et al demonstrated that acetylation of LKB1 occurs on several specific lysines, among which lysine 48 appears to be critical for mediating the effects of SIRT1 on LKB1 in HEK293 and HepG2 cells.11 Although Zu et al did not characterize the site-specific acetylation of LKB1 in ECs, it is possible that the acetylation signature of LKB1 is different in ECs, eg, as a result of differential expression and/or activity of lysine acetyltransferases (KATs). Regardless of this, it is noteworthy that several other senescence-regulating molecules are modulated by reversible acetylation and are targeted by SIRT1 such as p53, endothelial nitric oxide synthase and Foxo transcription factors.7,13–16 These observations raise the possibility that changes in lysine acetylation might provide an important regulatory switch in the complex processes of senescence and aging. By deacetylating several targets within the signaling network governing endothelial senescence, SIRT1 may exert robust control over this multistep process and thereby execute its protective effects on the vascular endothelium (Figure 2). Download figureDownload PowerPointFigure 2. Signaling networks of SIRT1 in endothelial senescence. SIRT1 protects ECs from premature senescence by directly and indirectly modulating the activity and expression of key endothelial homeostatic factors. During aging, miR-217 expression is induced in ECs, which inhibits SIRT1 mRNA expression and favors the development of endothelial senescence.A key question arising from this work is how SIRT1 expression is itself regulated in ECs. SIRT1 expression is positively and negatively regulated by several transcription factors and transcriptional cofactors including H1C1, CtBP, p53, Foxo, and E2F14,5 as well as by microRNAs such as miR-34, miR-199, miR-217, and miR-92a.17–20 Interestingly, miR-217, which inhibits SIRT1 expression through a miR-217-binding site within the 3′ untranslated region of the SIRT1 mRNA, is induced in aging ECs and promotes a premature senescence-like phenotype.19 Understanding the upstream factors that control the expression of SIRT1 will be essential to further unravel the relevance and function of the SIRT1/LKB1/AMPK signaling circuitry in ECs in development, homeostasis, and disease. Further investigations will also have to establish whether the modulation of the LKB1/AMPK pathway by SIRT1 is relevant in cardiovascular diseases such as atherosclerosis, in which the vasculature must withstand increased levels of oxidative and metabolic stress. Lastly, SIRT1, LKB1, and AMPK play additional roles in blood vessels beyond those in endothelial senescence. For example, SIRT1, LKB1, and AMPK have been implicated in the regulation of angiogenesis,14,21–23 which is the formation of new blood vessels from existing vasculature. Thus, studying the molecular interplay of this signaling circuitry might become a fertile ground for future investigations in several aspects of cardiovascular biology.Altogether, the study by Zu et al sheds new light on our understanding of endothelial senescence and vascular aging by illustrating the interdependent regulation of key energy- and stress-responsive regulators of EC homeostasis: SIRT1, LKB1, and AMPK. Although future studies will have to address the therapeutic usefulness, these results also suggest potential new pharmacological strategies to counteract age-related diseases of the cardiovascular system. Table 1. Non-standard Abbreviations and AcronymsAMPKAMP-activated protein kinaseECendothelial cellLKB1serine threonine kinase 11 (STK11)miRNAmicroRNASIRTsirtuinThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.The author apologizes to those authors whose relevant works were not cited because of space restrictions.Sources of FundingSupported by grants from the Deutsche Forschungsgemeinschaft (PO1306/1-1, SFB 834/A6, and Exc 147/1).DisclosuresNone.FootnotesCorrespondence to Michael Potente, MD, Institute for Cardiovascular Regeneration, Centre of Molecular Medicine & Department of Cardiology, Internal Medicine III, Goethe University, D-60590 Frankfurt (Main), Germany. E-mail [email protected] References 1 Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res. 2005; 66: 286–294.CrossrefMedlineGoogle Scholar2 Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007; 130: 223–233.CrossrefMedlineGoogle Scholar3 Zu Y, Liu L, Lee MY, Xu C, Liang Y, Man RY, Vanhoutte PM, Wang Y. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res. 2010; 106: 1384–1393.LinkGoogle Scholar4 Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009; 460: 587–591.CrossrefMedlineGoogle Scholar5 Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 5: 253–295.CrossrefMedlineGoogle Scholar6 Guarani V, Potente M. SIRT1 - a metabolic sensor that controls blood vessel growth. Curr Opin Pharmacol. 2010; 10: 139–145.CrossrefMedlineGoogle Scholar7 Ota H, Akishita M, Eto M, Iijima K, Kaneki M, Ouchi Y. Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J Mol Cell Cardiol. 2007; 43: 571–579.CrossrefMedlineGoogle Scholar8 Fulco M, Cen Y, Zhao P, Hoffman EP, McBurney MW, Sauve AA, Sartorelli V. Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell. 2008; 14: 661–673.CrossrefMedlineGoogle Scholar9 Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009; 458: 1056–1060.CrossrefMedlineGoogle Scholar10 Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007; 8: 774–785.CrossrefMedlineGoogle Scholar11 Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem. 2008; 283: 27628–27635.CrossrefMedlineGoogle Scholar12 Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y, Lan F, Walsh K, Wierzbicki M, Verbeuren TJ, Cohen RA, Zang M. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem. 2008; 283: 20015–20026.CrossrefMedlineGoogle Scholar13 Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB, DeRicco J, Kasuno K, Irani K. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 2007; 104: 14855–14860.CrossrefMedlineGoogle Scholar14 Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, Haendeler J, Mione M, Dejana E, Alt FW, Zeiher AM, Dimmeler S. SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 2007; 21: 2644–2658.CrossrefMedlineGoogle Scholar15 Borradaile NM, Pickering JG. Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environment. Aging Cell. 2009; 8: 100–112.CrossrefMedlineGoogle Scholar16 Gracia-Sancho J, Villarreal G Jr, Zhang Y, Garcia-Cardena G. Activation of SIRT1 by resveratrol induces KLF2 expression conferring an endothelial vasoprotective phenotype. Cardiovasc Res. 85: 514–519.CrossrefMedlineGoogle Scholar17 Yamakuchi M, Ferlito M, Lowenstein CJ. miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci U S A. 2008; 105: 13421–13426.CrossrefMedlineGoogle Scholar18 Rane S, He M, Sayed D, Vashistha H, Malhotra A, Sadoshima J, Vatner DE, Vatner SF, Abdellatif M. Downregulation of miR-199a derepresses hypoxia-inducible factor-1alpha and Sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes. Circ Res. 2009; 104: 879–886.LinkGoogle Scholar19 Menghini R, Casagrande V, Cardellini M, Martelli E, Terrinoni A, Amati F, Vasa-Nicotera M, Ippoliti A, Novelli G, Melino G, Lauro R, Federici M. MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation. 2009; 120: 1524–1532.LinkGoogle Scholar20 Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H, Doebele C, Ohtani K, Chavakis E, Potente M, Tjwa M, Urbich C, Zeiher AM, Dimmeler S. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 2009; 324: 1710–1713.CrossrefMedlineGoogle Scholar21 Ylikorkala A, Rossi DJ, Korsisaari N, Luukko K, Alitalo K, Henkemeyer M, Makela TP. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science. 2001; 293: 1323–1326.CrossrefMedlineGoogle Scholar22 Londesborough A, Vaahtomeri K, Tiainen M, Katajisto P, Ekman N, Vallenius T, Makela TP. LKB1 in endothelial cells is required for angiogenesis and TGFbeta-mediated vascular smooth muscle cell recruitment. Development. 2008; 135: 2331–2338.CrossrefMedlineGoogle Scholar23 Ouchi N, Shibata R, Walsh K. AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle. Circ Res. 2005; 96: 838–846.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Begum M, Konja D, Singh S, Chlopicki S and Wang Y (2021) Endothelial SIRT1 as a Target for the Prevention of Arterial Aging: Promises and Challenges, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0000000000001154, 78:6S, (S63-S77) Gao Y (2017) Aging and Vasoreactivity Biology of Vascular Smooth Muscle: Vasoconstriction and Dilatation, 10.1007/978-981-10-4810-4_19, (267-286), . Bai B, Vanhoutte P and Wang Y (2014) Loss-of-SIRT1 function during vascular ageing: Hyperphosphorylation mediated by cyclin-dependent kinase 5, Trends in Cardiovascular Medicine, 10.1016/j.tcm.2013.07.001, 24:2, (81-84), Online publication date: 1-Feb-2014. Chiara B, Ilaria C, Antonietta C, Francesca C, Marco M, Lucia A and Gilda C (2014) SIRT1 Inhibition Affects Angiogenic Properties of Human MSCs, BioMed Research International, 10.1155/2014/783459, 2014, (1-12), . Hara H, Araya J, Takasaka N, Fujii S, Kojima J, Yumino Y, Shimizu K, Ishikawa T, Numata T, Kawaishi M, Saito K, Hirano J, Odaka M, Morikawa T, Hano H, Nakayama K and Kuwano K (2012) Involvement of Creatine Kinase B in Cigarette Smoke–Induced Bronchial Epithelial Cell Senescence, American Journal of Respiratory Cell and Molecular Biology, 10.1165/rcmb.2011-0214OC, 46:3, (306-312), Online publication date: 1-Mar-2012. (2012) The Endothelium, Cardiovascular Disease, and Therapy Metabolic Syndrome and Cardiovascular Disease, 10.1002/9781118480045.ch14, (409-467), Online publication date: 29-Aug-2012. Wang Y, Xu C, Liang Y and Vanhoutte P (2012) SIRT1 in metabolic syndrome: Where to target matters, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2012.08.009, 136:3, (305-318), Online publication date: 1-Dec-2012. (2012) The FoxO Transcription Factors and Sirtuins Metabolic Syndrome and Cardiovascular Disease, 10.1002/9781118480045.ch4, (64-95), Online publication date: 29-Aug-2012. Wang Y, Liang Y and Vanhoutte P (2010) SIRT1 and AMPK in regulating mammalian senescence: A critical review and a working model, FEBS Letters, 10.1016/j.febslet.2010.11.047, 585:7, (986-994), Online publication date: 6-Apr-2011. Castrejón-Téllez V, Villegas-Romero M, Rubio-Ruiz M, Pérez-Torres I, Carreón-Torres E, Díaz-Díaz E and Guarner-Lans V (2020) Effect of a Resveratrol/Quercetin Mixture on the Reversion of Hypertension Induced by a Short-Term Exposure to High Sucrose Levels Near Weaning and a Long-Term Exposure That Leads to Metabolic Syndrome in Rats, International Journal of Molecular Sciences, 10.3390/ijms21062231, 21:6, (2231) April 30, 2010Vol 106, Issue 8 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCRESAHA.110.219352PMID: 20431073 Originally publishedApril 30, 2010 KeywordsAMPKLKB1SIRT1endothelial cellssenescencePDF download Advertisement