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Exp Physiol94.3 pp 305310 305

Experimental Physiology Symposium Report

Signalling processes in endothelial ageing in relationto chronic oxidative stress and their potentialtherapeutic implications in humans

Bernd van der Loo1, Stefan Schildknecht2, Rebecca Zee3 and Markus M. Bachschmid3

1Clinic of Cardiology, Cardiovascular Centre, Department of Medicine, University Hospital Zurich, Switzerland2Department of Biology, Faculty of Sciences, University of Konstanz, Germany3Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA

Ageing is an importantrisk factor for the developmentof cardiovasculardiseases. Vascular ageing

is mainly characterized by endothelial dysfunction, an alteration of endothelium-dependent

signalling processes and vascular remodelling. The underlying mechanisms comprise increased

production of reactive oxygen species (ROS), inactivation of nitric oxide (NO) and subsequentformation of peroxynitrite (ONOO). Elevated ONOO may exhibit new messenger functions

by post-translational oxidative modification of intracellular regulatory proteins. Mitochondria

are a major source of age-associated superoxide formation, as electrons are misdirected from

the respiratory chain. Manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant

enzyme, is an integral part of the nucleoids and may protect mitochondrial DNA from ROS.

A model linking NO, mitochondria, MnSOD and its acetylation/deacetylation by sirtuins

(NAD+-dependent class III histone deacetylases) may be the basis for a potentially new powerful

therapeutic intervention in the ageing process.

(Received 13 August 2008; accepted after revision 5 November 2008; first published online 7 November 2008)

Correspondingauthor B. van der Loo: Clinicof Cardiology, CardiovascularCentre,Departmentof Medicine,University

Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland. Email: [email protected]

Cardiovascular diseases have a higher incidence withincreasing age, even in the absence of establishedrisk factors. This suggests that ageing per se altersvascular function. Vascular ageing is mainly characterizedby endothelial dysfunction (van der Loo et al.2000), associated with decreased endothelium-dependentrelaxations with increasing age (Tschudiet al.1996). Theendothelium exerts a multimodal regulation of vasculartone, structure and function by the release of vasoactivesubstances, which, under physiological conditions, are

finely balanced to ensure vascular homeostasis. However,with increasing age, this equilibrium cannot be preservedanylonger. An age-associated enhancedsuperoxide (O2

)production in the vasculature (Oudot et al. 2006;van der Loo et al. 2000), mainly derived from theendothelium, occurs and is the basis for the oxidative-stress theory of vascular ageing. It is obvious thatreactive oxygen species (ROS) play a pivotal role inendothelial cell redox signalling. Knowledge about theirsources and the signalling cascades they modify, as wellas the compensatory mechanisms, will enhance our

knowledge of the vascular ageing process. The particularunderstanding about how redox systems are regulated inthe elderly may also help to identify new targets to treatageing, which is, besides smoking, diabetes, hypertensionand obesity, a major cardiovascular risk factor.

Endothelial dysfunction versusendothelial cell

activation

The endothelium controls homeostatic conditions by

the release of potent endothelium-derived autacoids.Endothelial cell properties and the signalling processesare altered in a variety of pathophysiological conditions,such as inflammation, exogenous noxious substances andageing. For the description of endothelial alterations,several terms and definitions have been used, such asendothelial dysfunction and endothelial cell activation(Cines et al. 1998). The latter is based on the factthat the endothelium is an integral part of the innateimmune system, controlling adhesion and transcytosis ofleukocytes and monocytes to the site of inflammation.

C2008 The Authors. Journal compilation C2009 The Physiological Society DOI: 10.1113/expphysiol.2008.043315

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306 B. van der Loo and others Exp Physiol94.3 pp 305310

Locally invading pathogens can trigger the release ofcytokines by tissue macrophages, thus activating theendothelium and guiding immune cells to the siteof inflammation. This involves the opening of theendothelial cellbarrier, reductionof the release of repellentmolecules, expression of adhesion molecules and finallythe controlled diapedesis of immune cells. This process is

a fully reversible physiological reaction to inflammationor injury, but chronic exposure to ROS, as in the ageingprocess, may lead to irreversible changes and damage ofthe endothelial cell layer.

At the molecular level, two subsequent strictly timedphases can be distinguished and are called endothelialcell activation (ECA) type I and type II. The first phase(ECA type I), in which endothelial cells retract from eachother, express P-selectin (Prescottet al.2001) and releasethe von Willebrand factor, is entirely independent ofdenovoprotein synthesis and essentially completed within1 h. We suggested an inhibition of nitric oxide (NO)

and prostaglandin I2 production by a novel mechanisminvolving peroxynitrite (ONOO) formation from NOand a still unknown source of O2

radicals (Ullrich &Bachschmid, 2000). Peroxynitrite then causes tyrosinenitration and concomitant inhibition of prostaglandinsynthase (PGIS; Ullrich & Bachschmid, 2000). This leadsto accumulation of prostaglandin H2, which is able toactivate the thromboxane A2/prostaglandin H2 receptor,mediating bothsmooth muscle contraction and activationof platelets and white cells.

A second stage (ECA type II)becomes apparent after 1 hand involves induction and expression of early genes, suchas the adhesion molecules intracellular adhesion moleculeor vascular cell adhesion molecule and proinflammatorycytokines, as well as regulatory enzymes such as nitricoxide synthase 2 (NOS 2) and cyclo-oxygenase 2 (COX-2). As a consequence, white cells can tightly adhere andmigrate into tissues, NO and prostaglandins are formedin excess, and cytokines orchestrate the inflammatoryresponse.

It is crucial to understand the molecular mechanismsbehind endothelial cell activation in order to developpharmacological strategies to prevent this process or,more importantly, to induce resolution and reversal ofinflammation.

Free radicals and vascular ageing

Nitric oxide is one of the most important mediatorsof the cardiovascular system and has been extensivelystudied. Pathophysiologically, endothelial dysfunction isdescribed as a paradoxical response of the vasculatureto acetylcholine, reacting with constriction instead ofrelaxation. Normally, acetylcholine triggers the specificendothelium-derived release of NO, leading to vascular

relaxation. Studies on ageing in animal models andhumans have proven that the bioavailability of NO iscontinuously diminished and, in parallel, endothelium-derivedO2

increases (van der Looet al.2000; Krause,2007).

Superoxide is a highly efficient scavenger for NO,causing formation of the very reactive and deleterious

ONOO in a neardiffusion-controlled reaction(Beckman& Koppenol, 1996). At high concentrations (micromolarrange), peroxynitrite oxidizes unspecifically any biologicalmacromolecule, such as DNA, proteins and lipids. Atlower concentrations (nanomolar), it interferes withimportant vascular signalling pathways, such as NO andprostaglandin signalling, calcium homeostasis, mitogen-activatedproteinkinase cascade, nuclear factorB(NFB)and activator protein 1 (Xie et al. 2006). Thus anincrease in O2

and subsequent peroxynitrite formationreduces the bioavailability ofNO and leads to endothelialdysfunction, one of the major causes for the progression

of vascular disease and senescence.When studying the distribution of 3-nitrotyrosine

residues, a typical end-product of the reaction of ONOO

with biological compounds, by using immunogoldlabelling and electron microscopy, we found themost significant accumulation of nitrotyrosine in themitochondria, suggesting primarily a mitochondrialsource of O2

(van der Loo et al. 2000). However,other potential sources of O2

production, such assubunits of the NADPH oxidase (Krause, 2007), xanthineoxidase, and an uncoupled endothelial (e)NOS (NOS-3) have to be considered. Both upregulation of eNOS(van der Loo et al. 2000) and reduced levels of enzymeexpression (Cernadas et al. 1998) have been observedwith increasing age. Our own data demonstrating a steepincrease both in expression and in activity of eNOSsupport theconceptthat eNOS may, as an oxidase,becomepart of a redox system that increases electron transfer tomolecular oxygen.

The role of mitochondria

Under physiologicalconditions, approximately 0.1%of O2consumedby mitochondria is reduced to O2

(Fridovich,

2004).Age-associated mitochondrial dysfunction implies

increased generation of O2 and peroxynitrite by

misdirection of electrons from the respiratory chaininto ROS production due to a decline of mitochondrialfunction (van der Loo et al. 2000), such as inactivationof aconitase, reduced ATP synthesis and enhancedpermeability transition pore opening, leading toapoptosis. This initiates a vicious cycle of increased(nuclear and mitochondrial) DNA damage, leading againto moreROS generation, entailing further mitochondrial

C2008 The Authors. Journal compilation C2009 The Physiological Society



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Exp Physiol94.3 pp 305310 Endothelial ageing 307

DNA (mtDNA) damage (Finkel & Holbrook, 2000;Fig. 1). Mitochondrial DNA is considered to be farmore susceptible to oxidative stress than nuclear DNAbecause of the proximity of mtDNA to the source offree oxygen radicals, because protective mitochondrialhistoneproteinsare absent (Larsenetal. 2005)andbecausemitochondria lack efficient DNA repair mechanisms

(Larsenet al. 2005). Interestingly, experimental evidencein Caenorhabditis elegans has also been provided for adirect link between mitochondrial ROS generation andnuclear (genomic) DNA damage (Hartman et al. 2004).However, the exact signalling pathways determining themolecular basis for the link between lifelong damage tomtDNA and age-associated vascular dysfunction are notyet fully understood.

Figure 1. Formation of mitochondrial reactive oxygen and nitrogen species

Abbreviations: NO, nitric oxide; ONOO, peroxynitrite; O2, superoxide; TOM, translocase of the outer

membrane; MnSOD, manganese superoxide dismutase; GSH, reduced glutathione; GSSG, oxidized glutathione;

CCS, copper chaperone for Cu,Zn superoxide dismutase; Q, ubiquinone or coenzyme Q10; and IMS,

intermembrane space. The mitochondrialrespiratory chain continuously shuttles complex I or II-derived electrons via

ubiquinone, complex III and cytochromecto complex IV (cytochromecoxidase). The terminal complex IV transfers

electrons to molecular oxygen (O2), producing water (H2O). Complexes I, III and IV use the energy from theelectrons to create the electrochemical gradient by pumping protons across the inner mitochondrial membrane for

ATP synthesis at complex V (oxidative phosphorylation). Electron leaks at complex I, III and ubiquinone lead to O2

formation, which is sequentially detoxified by MnSOD, glutathione peroxidase and mitochondrial peroxiredoxins or

glutaredoxin. Changes in the mitochondrial GSH/GSSG ratio can cause protein glutathiolation, which in the case of

complex I results in inhibition. Mitochodrial NO maybe derived from a mitochondrial nitric oxide synthase isoform,

from nitrite reduction at complex III or may diffuse from the outside into the mitochondria. Nitric oxide combines

with mitochondrial O2 to form the highly reactive peroxynitrite, which may nitrate and inactivate MnSOD,

cause mtDNA lesions or diffuse into the cytosol. Oxidative mtDNA lesions promote mutation and dysfunction

of respiratory chain components, thus enhancing free radical formation and mitochondrial dysfunction. In order

to compensate for an age-dependent increase in mitochondrial superoxide formation, newly synthesized and

unfolded Cu,ZnSOD can translocate into the mitochondrial intermembrane space, where it is then folded and

loaded with Zn and Cu in order to shield the cytosol from O2.

Antioxidant systems and compensatory mechanisms

Based upon the oxidative stress hypothesis of vascularageing, naturally occurring antioxidants such as vitaminswould seem to be attractive candidates to prevent ROSproduction. Vitamin E is an important electron sourcefor the reduction of ONOO (Leeet al.1998). However,

in aged rats fed a normal diet and not susceptibleto atherosclerosis, -tocopherol, the biologically mostactive form of vitamin E, was found to be markedlyincreased in both plasma and major organs. The highest,up to 70-fold, increase was found in the aortic wall(van der Loo et al. 2002). This suggests that sufficientlyhigh levels of antioxidant vitamin E may be built upfrom a normal diet in an attempt to counterbalance


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age-associated oxidative stress and that this may representa self-regulatory protective adaptation.

In physiological conditions, antioxidant enzymesprevent the detrimental effects of O2

. Apartfrom mitochondrial manganese superoxide dismutase(MnSOD; Sod 2), extracellular superoxide dismutase(EC-SOD; Sod 3) is the main scavenger of O2

in the extracellular space and Cu,Zn superoxidedismutase (Cu,ZnSOD; Sod 1) in the cytosol, respectively.Copper/zinc superoxide dismutase (Cu,ZnSOD) wasrecently shown to lose its membrane and caveolaeassociation and to relocate to the mitochondria inan age-dependent manner (van der Loo et al. 2006).Unlike MnSOD, constitutively expressedin mitochondria,Cu,ZnSOD is not inactivated by ONOO-mediatedtyrosine nitration as a function of age. The processmay be regulated by age-dependent elevated O2

levelsof copper chaperone for superoxide dismutase in the

Figure 2. Cytosolic control of mitochondrial ROS formation and effects of sirtuins

Abbreviations: SIRT, sirtuin, Ac, acetylation; ROS, reactive oxygen species; MnSOD, manganese superoxide

dismutase; Gpx, glutathione peroxidase; and mTFA, mitochondrial transcription factor A. Various signalling

cascades can affect mitochondrial physiology, mediate mitochondrial radical formation or are connected to

apoptotic signalling. Oxidative stress activates protein kinase C, leading to serine-phosphorylation of the adaptor

protein p66Shc, which subsequently translocates to the mitochondrial intermembrane space and associates withthe

translocator inner membrane-outer membrane (TIM-TOM) l protein import complex. Proapoptotic stimuli releasep66Shc from the complex and, via interaction with cytochrome c, hydrogen peroxide is formed, which triggers the

permeability transition pore and initiates apoptosis. Mitochondrial translocation has also been reported for p53

a transcription factor promoting senescence and p21Ras a signaling molecule involved in cell cycle regulation.

Both molecules are assumed to sequester antiapoptotic proteins of the Bcl-mammalian gene family regulating

mitochondrial membrane permeabilization thus promoting free radical formation and apoptosis. Furthermore,

the stability of p53 is regulated by lysine-acetylation, which competes with ubiquitinylation and subsequent

proteasomal degradation. Reactive oxygen species may inactivate SIRT1 by oxidation of an essential structural

Zn-finger that may result in p53 accumulation and mitochondrial translocation. Another example is tumour

necrosis factor signalling, which involves the ceramide pathway that increases mitochondrial superoxide formation

at complex III. Mitochondria also respond very sensitively to oxidative stimuli or metabolic cues with enhanced

electronleakageand freeradical formation. Thismay alter the composition of mitochondrial nucleoids and protein

DNA complexes, and increase the mtDNA mutation rate. Similar to organization of nuclear DNA, mitochondrial

sirtuins may regulate nucleoid plasticity.

intermembranespace, resultingin retention of Cu,ZnSODin the mitochondria. Thus, the enzyme becomespart of a compensatory defense against compromisedmitochondrial function.

Sirtuins in vascular ageing

Sirtuins (SIRT, silent information regulator two) area class of NAD+-dependent protein deacetylases andare known to be able to increase lifespan bymechanisms similar to calorie restriction (Bordone& Guarente, 2005). These mechanisms include, mostimportantly, the control of glucose metabolism inhepatocytes by modulation (deacetylation) of PGC-1 [PPAR (peroxisome proliferator-activated receptor) coactivator 1; Rodgers et al. 2005] and suppression ofPPAR-controlled genes involved in the regulation offat tissue (Picard et al. 2004). At least seven isoforms,




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Exp Physiol94.3 pp 305310 Endothelial ageing 309

exerting diverse functions, exist in humans. By far thebest investigated of the homologues so far is SIRT1,which deacetylates p53, a well-known transcription factorpromoting senescence, therebylimiting premature cellularsenescence (Langley et al. 2002). Resveratrol is one ofthe polyphenols found in red wine and responsible forcardiovascular protective effects (Opie & Lecour, 2007).

Resveratrol has been shown to be able to activate SIRT1(but not other sirtuin homologues) by promoting aconformational change in the enzyme (Borraet al.2005).Resveratrol can extend lifespan in yeast and in miceon a high-calorie diet (Baur et al. 2006), indicatinga potentially new powerful intervention in the ageingprocess. Treatment of mice with resveratrol leads toan increase in mitochondrial size, enzymatic activity,mtDNA content and enrichment of genes involved inmitochondrial biogenesis in skeletal muscle (Lagougeet al. 2006). These effects on mitochondrial functionare mediated by SIRT1 and PGC-1, with SIRT1

deacetylating and thereby activating PGC-1 (Lagougeet al. 2006). A recent study in mice on a high-fat dietmoderately overexpressing SIRT1 proved that SIRT1 canlower lipid-induced inflammation and improve glucosetolerance. In part, these effects are mediated by down-modulation of NFB, resulting in reduced activationof proinflammatory cytokines such as tumour necrosisfactor and interleukin-6 and an increased expressionof MnSOD (Pfluger et al. 2007). The effects of anatural compound on lifespan will certainly lead to thedevelopment of more potent analogues of resveratrol forin vivouse in the future (Koo & Montminy, 2006).

Interestingly, calorie restriction was also recentlyshown to induce eNOS expression in various mousetissues, accompanied by a promotion of mitochondrialbiogenesis, increased mtDNA content and SIRT1expression, dependent on eNOS-derived NO (Nisoliet al. 2005). Furthermore, in a model (treatment ofhuman umbilical vein endothelial cells with hydrogenperoxide) of stress-induced premature senescence, theselective phosphodiesterase 3 inhibitor cilostazol reducedthe senescent cell phenotype by upregulation of SIRT1(Ota et al. 2008). These findings may lead to a recentlyproposed model linking calorie restriction, NO, SIRT1and activation of mitochondria (Guarente, 2005).

Therefore, the development of SIRT1 activators maypotentially be highly beneficial for the aged cardiovascularsystem in order to restore endothelial function byactivating eNOS and by reducing mitochondrial O2

formation via induction of MnSOD expression.

A mechanistic concept of age-associated

mitochondrial dysfunction

Mitochondrial proofreading-deficient polymerase (Pol) knock-in mice have been shown to accumulate

mtDNA mutations and deletions, resulting in prematureageing (Trifunovic et al. 2004; Kujoth et al. 2005).Protective mechanisms must exist within the nucleoids toshield mtDNA from ROS produced by the nearby electrontransport chain. Manganese superoxide dismutase, anantioxidant enzyme localized in the mitochondria, hasbeen demonstrated to be an integral component of

the nucleoids, where it can protect mtDNA from ROS(J. Kienhoefer & M. Bachschmid, unpublished data).Manganese superoxide dismutase can be acetylated,which may modulate its association to mtDNA (Kimet al.2006), in analogy to the control of nuclear chromatinplasticity by histone acetylation/deacetylation.

Mitochondria harbour three sirtuin isoforms which, bydeacetylation, may increase the association of MnSODand other protective proteins with mtDNA and mayregulate replication and transcription of mtDNA bymodulating the composition and density of the nucleoids.Peroxynitrite can inactivate SIRT1, presumably via

disruption of the zinc finger (Min et al. 2001). Thissuggests that sirtuins are sensitive to ROS and can losetheirabilityto maintainmtDNA in a more protected form.Finally, with an increasing rate of mutations in mtDNA,this will lead to a malfunctioning respiratory chain andenhanced ROS generation within mitochondria, similarto the effects seen in Polproofreading-deficient miceexhibiting the features of premature ageing (Trifunovicet al.2004; Kujothet al.2005; Fig. 2).

If this concept holds true, the potential therapeuticimplications to combat the loss of protection of mtDNAagainst ROS may have an enormous impact.

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Exp Physiol 2009 Van Der Loo 305 10