Abstract
Vascular aging plays a central role in health problems and mortality in older people. Apart from the impact of several classical cardiovascular risk factors on the vasculature, chronological aging remains the single most important determinant of cardiovascular problems. The causative mechanisms by which chronological aging mediates its impact, independently from classical risk factors, remain to be elucidated. In recent years evidence has accumulated that unrepaired DNA damage may play an important role. Observations in animal models and in humans indicate that under conditions during which DNA damage accumulates in an accelerated rate, functional decline of the vasculature takes place in a similar but more rapid or more exaggerated way than occurs in the absence of such conditions. Also epidemiological studies suggest a relationship between DNA maintenance and age-related cardiovascular disease. Accordingly, mouse models of defective DNA repair are means to study the mechanisms involved in biological aging of the vasculature. We here review the evidence of the role of DNA damage in vascular aging, and present mechanisms by which genomic instability interferes with regulation of the vascular tone. In addition, we present potential remedies against vascular aging induced by genomic instability. Central to this review is the role of diverse types of DNA damage (telomeric, non-telomeric and mitochondrial), of cellular changes (apoptosis, senescence, autophagy), mediators of senescence and cell growth (plasminogen activator inhibitor-1 (PAI-1), cyclin-dependent kinase inhibitors, senescence-associated secretory phenotype (SASP)/senescence-messaging secretome (SMS), insulin and insulin-like growth factor 1 (IGF-1) signaling), the adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-nuclear factor kappa B (NFκB) axis, reactive oxygen species (ROS) vs. endothelial nitric oxide synthase (eNOS)-cyclic guanosine monophosphate (cGMP) signaling, phosphodiesterase (PDE) 1 and 5, transcription factor NF-E2-related factor-2 (Nrf2), and diet restriction.
Highlights
Cardiovascular diseases (CVD) are the leading cause of death worldwide, responsible for killing 17.3 million persons per year [1]
There is ample evidence that genomic instability is involved in vascular aging in humans
This finding suggests that in Ercc1d/ ́ mice, a mouse model for accelerated aging due to genomic instability, PDE1 has a stronger role than PDE5 in regulating cyclic guanosine monophosphate (cGMP) signaling and vasomotor function [113]; at least, it undergoes stronger regulation, because cellular senescence was shown to be strongly associated with increased expression of both PDE1A and C subtypes, and to a lesser extent with PDE5, in human cultured vascular smooth muscle cells (VSMCs)
Summary
Cardiovascular diseases (CVD) are the leading cause of death worldwide, responsible for killing 17.3 million persons per year [1]. The onset of CVD is triggered by vascular endothelial alterations characterized by an impaired endothelium-dependent vasodilation, the overproduction of prIont-.iJn. Mflaolm. Age is the st2roofn25gest independent predictor for CVD in risk scores in middle-aged persons, and an important determinant for cianrddeipoevnadscenutlarprheedaiclttohrinfotrheCpVoDpuinlatrioisnk asgceodres65inormoildddelre-[a3g,4e]d. INtriOc iosxicdreuc(iNalOi)n [t5h,6e].mNaiOntiesnacrnucceiaol fivnatshceular homemoasitnatseinsa, nincecluodf invgasicnutlahre rheogmuelaotsitoansiso, f ivnacslucudilnagr diinlattihoen,rtehgeumlatoiodnulaotfiovnasocfuclaerll gdriloawtiothn,anthdethe prevemnotidounlaotfiotnhroofmcbeollsigsr[o7w].tIhn athned atbhseenpcreevoefnatihonealotfhythernodmobtohseisliu[m7]., tIhnestheefaacbtosersncgeraodfuaallhyeainltchryease the peantdhootlhoegliicumph, ethneosteyfpaectoofrsthgeravdausaclulylaintucrreeauseptthoetphaethpooliongticthpahtecnaortdypioevoafstchuelavrasecvuelnattusroecucuprt.o the pWoihnitlethtaht icsarpdaiorvaadsicgumlareexvpelnatisnosccvuars.cular aging in view of classical risk factors as causative mmeecchhmmaaeenncciihhssWtmaainnchsiiia,ssltmlaeitcesrtr,ehanacilseatrentepirctvnaleyearnasttpidlvfyroiegoprsmpruoofnopsedrexodpesuerlaadsniltdntaaeeslntrrednsvrtiaanantsnaigctvduitveilhnaevgerviepiatewgrhwoiencoogenpnsrsivvonaoacsesfvccsivuuseawllasaorcrfouaafglvgaiacnirslngacagsughslhiiaancasragsel am[er8gmie]sin.rkeggIrenfgda[etc8htdt]hoi.satrhstInnapoatrsvetphsecreliaesnpusteassnanrnotatviesdvweenilgemw, causaplamraedcihgman,iscmaussafol rmtheechparnoicsmesss ofofragthinegpirtosceelfs,smoof satgniontgabitlsyelgf,enmoomsticniontsatbalbyiligteyn, oinmcliuc dininstgabteilliotym, ere attritiinocnlu, ddirnigveteltohme edreetartitmriteinonta, ldcrihvaentgheesdoetcrciumrernintagl cinhacnregaessinocgcluyrrwinigthin(cbrieoalsoinggiclyalw) iatghin(bgio(lFogigicuarle) 1). SItnabaidlidtyitioinn, vwaescpurleasrenatgimnge.chIanniasdmdsittihorno,uwghe wphreicshengtenmoemchicaninissmtasbiltihtryoguegnherwatheischthegefunnomcticonal chanignesstatbhialittyargeentyepraitceasl tfhoer ftuhnecatigoinnagl cvhaasncguelsatuharet .are typical for the aging vasculature. The survival response may or mhuatavteiobnesnehfeicrieailn(inneceredassetod bNeref2s-traebgluislahteedd. IGF-1 signaling, pro-inflammatory status) effects (see text and Ref. [8])
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